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1

Macrophage immunomodulatory activity of polysaccharides isolated from Opuntia polyacantha.  

PubMed

Opuntia polyacantha (prickly pear cactus) has been used extensively for its nutritional properties; however, less is known regarding medicinal properties of Opuntia tissues. In the present study, we extracted polysaccharides from O. polyacantha and used size-exclusion chromatography to fractionate the crude polysaccharides into four polysaccharide fractions (designated as Opuntia polysaccharides C-I to C-IV). The average M(r) of fractions C-I through C-IV was estimated to be 733, 550, 310, and 168 kDa, respectively, and sugar composition analysis revealed that Opuntia polysaccharides consisted primarily of galactose, galacturonic acid, xylose, arabinose, and rhamnose. Analysis of the effects of Opuntia polysaccharides on human and murine macrophages demonstrated that all four fractions had potent immunomodulatory activity, inducing production of reactive oxygen species, nitric oxide, tumor necrosis factor alpha, and interleukin 6. Furthermore, modulation of macrophage function by Opuntia polysaccharides was mediated, at least in part, through activation of nuclear factor kappaB. Together, our results provide a molecular basis to explain a portion of the beneficial therapeutic properties of extracts from O. polyacantha and support the concept of using Opuntia polysaccharides as an immunotherapeutic adjuvant. PMID:18597716

Schepetkin, Igor A; Xie, Gang; Kirpotina, Liliya N; Klein, Robyn A; Jutila, Mark A; Quinn, Mark T

2008-10-01

2

Immunomodulatory Effects of Liriope Platyphylla Water Extract on Lipopolysaccharide-Activated Mouse Macrophage  

PubMed Central

The tuber of Liriope platyphylla Wang et Tang (Liliaceae), also known as Liriopis tuber, is famous in Oriental medicine owing to its tonic, antitussive, expectorant and anti-asthmatic properties. In the present study, the effects of Liriopis tuber water extract (LP) on proinflammatory mediators secreted from lipopolysaccharide (LPS)-induced cultured RAW 264.7 mouse macrophages were investigated. Nitric oxide (NO), prostaglandin E2 (PGE2) and intracellular calcium release were measured after 24 h incubation. Various cytokines and nuclear transcription factors (NF-?B and CREB) of LPS-induced RAW 264.7 were measured by a multiplex bead array assay based on xMAP technology. LP (up to 200 ?g/mL) significantly decreased levels of nitric oxide (NO), interleukin (IL)-6, IL-10, IL-12p40, interferon-inducible protein-10, keratinocyte-derived chemokine, monocyte chemotactic protein-1, vascular endothelial growth factor, granulocyte macrophage-colony stimulating factor, platelet derived growth factor, PGE2, intracellular calcium, NF-?B and CREB in LPS-induced RAW 264.7 cells (p < 0.05). The results suggest that LP has immunomodulatory activity to reduce excessive immune reactions during the activation of macrophages by LPS. Further studies are needed to verify the precise mechanism regulating immunomodulatory activities of LP. PMID:23201926

Kim, Hye Kyung; Lee, Ji Young; Han, Hyo-Sang; Kim, Young-Jin; Kim, Hyun Joo; Kim, Yoon-Sang; Kim, Hyung Min; Ko, Seong-Gyu; An, Hyo-Jin; Lee, Young-Jong; Park, Wansu

2012-01-01

3

Assessment of Immunomodulatory Activity of Euphorbia hirta L.  

PubMed

Immune system is the major target for development of treatment strategies to improve the management of infections. Many species of Indian medicinal plants have been reported to possess active principles with immunomodulating properties. Euphorbia hirta, a pantropic herb has been reported to be pharmacologically active. This study reports one another not widely reported property of the plant, immunomodulatory activity, which has been proved using simple techniques like the macrophage activity testing, carbon clearance test and mast cell de-granulation assay. PMID:21694995

Ramesh, K Vijaya; Padmavathi, K

2010-09-01

4

Effects of Pouteria cambodiana extracts on in vitro immunomodulatory activity of mouse immune system.  

PubMed

Immunomodulatory activity of water and acetone extracts of stem bark of Pouteria cambodiana was examined on murine macrophage phagocytosis [nitroblue tetrazolium (NBT) dye reduction and lysosomal enzyme activity] and proliferation of splenocytes and bone marrow cells by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay with and without lipopolysaccharide (LPS) or pokeweed mitogen (PWM). Both aqueous and acetone extracts presented immunomodulatory activity without clear dose response relationship. PMID:16546328

Manosroi, Aranya; Saraphanchotiwitthaya, Aurasorn; Manosroi, Jiradej

2006-04-01

5

Immunomodulatory activity of polysaccharides isolated from Alchornea cordifolia  

PubMed Central

Ethnopharmacological relevance Extracts of leaves from different species of the genus Alchornea have been used for centuries to treat a variety of medicinal problems in tropical Africa. However, little is known about the high-molecular weight active components conferring therapeutic properties to these extracts. Objective The aim of this study was to evaluate the immunomodulatory activity of polysaccharides isolated from the leaves of Alchornea cordifolia. Materials and methods Water-soluble polysaccharides from leaves of A. cordifolia were extracted and fractionated by DEAE-cellulose, Diaion HP-20, and size-exclusion chromatography. Molecular weight, sugar analysis, and other physical and chemical characterization of the fractions were performed. Immunomodulatory activity of the polysaccharide fractions was evaluated by determining their ability to induce monocyte/macrophage nitric oxide (NO) and cytokine production. Activation of mitogen activated protein kinases (MAPK) was also assessed using a phospho-MAPK array. Activation of nuclear factor ?B (NF-?B) was measured using an alkaline phosphatase reporter gene assay in THP1-Blue monocytic cells. Results Six polysaccharide fractions from A. cordifolia were isolated. Fractions containing type II arabinogalactan had potent immunomodulatory activity. Particularly, the parent fraction AP-AU and its high-molecular weight sub-fraction AP-AU1 (average Mr was estimated to be 39.5 kDa) induced production of NO and cytokines [interleukin (IL)-1?, -6, -10, tumor necrosis factor (TNF)-?, and granulocyte macrophage-colony stimulating factor (GM-CSF)] in human peripheral blood mononuclear cells and human and murine monocyte/macrophages cell lines in vitro. Furthermore, treatment with AP-AU1 induced phosphorylation of Akt2, p38?/p38?, p70S6K1, RSK2, and mTOR, as well as stimulation of NF-?B transcriptional activity. Conclusion Our results provide a molecular basis to explain a portion of the beneficial therapeutic properties of water extracts from A. cordifolia leaves in traditional folk medicine of Africa. PMID:23291534

Kouakou, Koffi; Schepetkin, Igor A.; Yapi, Ahoua; Kirpotina, Liliya N.; Jutila, Mark A.; Quinn, Mark T.

2013-01-01

6

Ergot alkaloid glycosides with immunomodulatory activities  

Microsoft Academic Search

New glycosides derived from ergot alkaloids elymoclavine and DH-lysergol were synthesized by chemoenzymatic methods. ?-Glucosides were obtained either by chemical method or by transglycosylation (glycosidase from Aspergillus oryzae), lactosides were prepared by further extension of carbohydrate chain using ?-1,4-galactosyltransferase (bovine milk) and ?-5-N-acetylneuraminyl-(2?6)-?-d-galactopyranosyl-(1?4)- 2-acetamido-2-deoxy-?-d-glucopyranosyl-(1?O)-elymoclavine was prepared using ?-2,6-sialyltransferase (rat liver). Immunomodulatory activity of elymoclavine and 9,10-dihydrolysergol and their glycosylated derivatives

Vladimír K?en; Anna Fišerová; Claudine Augé; Petr Sedmera; Vladimír Havlí?ek; Petr Šíma

1996-01-01

7

The in vitro immunomodulatory activity of a polysaccharide isolated from Kadsura marmorata.  

PubMed

Kadsura marmorata has been used in traditional Chinese medicine as one of the major ingredients for the treatment of bronchial asthma, eczema, and acute and chronic infection due to either viruses or bacteria. The purpose of this study was to determine the immunomodulatory activities of the Kadsura polysaccharide (KPS) that was isolated and purified from the fruit of K. marmorata, designated as KPSIII and has a molecular weight of 130,406. The immunomodulatory effects of KPSIII were evaluated in vitro on chicken lymphocytes and macrophages. The results indicated that KPSIII could stimulate the cell proliferation of chicken T-lymphocytes, B-lymphocytes, and peritoneal macrophages and could significantly enhance cytokine secretion. Moreover, KPSIII regulated cytokine expression in T-lymphocytes and peritoneal macrophages. This study suggests that KPSIII has potential effects on regulating the immune system and might be an immunotherapeutic agent in treating various immunity-related diseases in chickens. PMID:23911505

Wang, Hongjun; Deng, Xuming; Zhou, Tiezhong; Wang, Chunhua; Hou, Yanjie; Jiang, Hong; Liu, Guangliang

2013-09-12

8

Immunomodulatory Activity of Chlorophytum borivilianum Sant. F  

PubMed Central

Chlorophytum borivilianum Santapau & Fernandes (Liliaceae) is a very popular herb in traditional Indian medicine and constitute a group of herbs used as ‘Rasayan’ or adaptogen. Ethanolic extract of the roots and its sapogenin were evaluated for their immunomodulatory activity. Effect of azathioprine-induced myelosuppresion and administration of extracts on hematological and serological parameters was determined. Administration of extracts greatly improved survival against Candida albicans infection. An increase in delayed-type hypersensitivity response (DTH), % neutrophil adhesion and in vivo phagocytosis by carbon clearance method was observed after treatment with extracts. Immunostimulant activity of ethanolic extract was more pronounced as compared to sapogenins. The results, thus justifies the traditional use of C. borivilianum as a rasayana drug. PMID:18227908

Thakur, Mayank; Bhargava, Shilpi

2007-01-01

9

Immunomodulatory Activity of Chlorophytum borivilianum Sant. F.  

PubMed

Chlorophytum borivilianum Santapau & Fernandes (Liliaceae) is a very popular herb in traditional Indian medicine and constitute a group of herbs used as 'Rasayan' or adaptogen. Ethanolic extract of the roots and its sapogenin were evaluated for their immunomodulatory activity. Effect of azathioprine-induced myelosuppresion and administration of extracts on hematological and serological parameters was determined. Administration of extracts greatly improved survival against Candida albicans infection. An increase in delayed-type hypersensitivity response (DTH), % neutrophil adhesion and in vivo phagocytosis by carbon clearance method was observed after treatment with extracts. Immunostimulant activity of ethanolic extract was more pronounced as compared to sapogenins. The results, thus justifies the traditional use of C. borivilianum as a rasayana drug. PMID:18227908

Thakur, Mayank; Bhargava, Shilpi; Dixit, V K

2007-12-01

10

Immunomodulatory Effects of Yersinia pestis Lipopolysaccharides on Human Macrophages ?  

PubMed Central

In the current study, we investigated the activity of lipopolysaccharide (LPS) purified from Yersinia pestis grown at either 27°C or 37°C (termed LPS-27 and LPS-37, respectively). LPS-27 containing hexa-acylated lipid A, similar to the LPS present in usual gram-negative bacteria, stimulated an inflammatory response in human U937 cells through Toll-like receptor 4 (TLR4). LPS-37, which did not contain hexa-acylated lipid A, exhibited strong antagonistic activity to the TLR4-mediated inflammatory response. The phagocytic activity in the cells was not affected by LPS-37. To estimate the activity of LPS in its bacterial binding form, formalin-killed bacteria (FKB) were prepared from Y. pestis cells grown at 27°C or 37°C (termed FKB-27 and FKB-37, respectively). FKB-27 strongly stimulated the inflammatory response. This activity was suppressed in the presence of an anti-TLR4 antibody but not an anti-TLR2 antibody. In addition, this activity was almost completely suppressed by LPS-37, indicating that the activity of FKB-27 is predominantly derived from the LPS-27 bacterial binding form. In contrast, FKB-37 showed no antagonistic activity. The results arising from the current study indicate that Y. pestis causes infection in humans without stimulating the TLR4-based defense system via bacterial binding of LPS-37, even when bacterial free LPS-37 is not released to suppress the defense system. This is in contrast to the findings for bacteria that possess agonistic LPS types, which are easily recognized by the defense system via the bacterial binding forms. PMID:19889939

Matsuura, Motohiro; Takahashi, Hideyuki; Watanabe, Haruo; Saito, Shinji; Kawahara, Kazuyoshi

2010-01-01

11

Antimicrobial and Immunomodulatory Activities of PR-39 Derived Peptides  

PubMed Central

The porcine cathelicidin PR-39 is a host defence peptide that plays a pivotal role in the innate immune defence of the pig against infections. Besides direct antimicrobial activity, it is involved in immunomodulation, wound healing and several other biological processes. In this study, the antimicrobial- and immunomodulatory activity of PR-39, and N- and C-terminal derivatives of PR-39 were tested. PR-39 exhibited an unexpected broad antimicrobial spectrum including several Gram positive strains such as Bacillus globigii and Enterococcus faecalis. Of organisms tested, only Staphylococcus aureus was insensitive to PR-39. Truncation of PR-39 down to 15 (N-terminal) amino acids did not lead to major loss of activity, while peptides corresponding to the C-terminal part of PR-39 were hampered in their antimicrobial activity. However, shorter peptides were all much more sensitive to inhibition by salt. Active peptides induced ATP leakage and loss of membrane potential in Bacillus globigii and Escherichia coli, indicating a lytic mechanism of action for these peptides. Finally, only the mature peptide was able to induce IL-8 production in porcine macrophages, but some shorter peptides also had an effect on TNF-? production showing differential regulation of cytokine induction by PR-39 derived peptides. None of the active peptides showed high cytotoxicity highlighting the potential of these peptides for use as an alternative to antibiotics. PMID:24755622

Veldhuizen, Edwin J. A.; Schneider, Viktoria A. F.; Agustiandari, Herfita; van Dijk, Albert; Tjeerdsma-van Bokhoven, Johanna L. M.; Bikker, Floris J.; Haagsman, Henk P.

2014-01-01

12

Ergot alkaloid glycosides with immunomodulatory activities.  

PubMed

New glycosides derived from ergot alkaloids elymoclavine and DH-lysergol were synthesized by chemoenzymatic methods. beta-Glucosides were obtained either by chemical method or by transglycosylation (glycosidase from Aspergillus oryzae), lactosides were prepared by further extension of carbohydrate chain using beta-1,4-galactosyltransferase (bovine milk) and alpha-5-N-acetylneuraminyl-(2-->6)-beta-D-galactopyranosyl-(l-->4)-2- acetamido-2-deoxy-beta-D-glucopyranosyl-(1-->O)-elymoclavine was prepared using alpha-2,6-sialyltransferase (rat liver). Immunomodulatory activity of elymoclavine and 9,10-dihydrolysergol and their glycosylated derivatives on natural killer (NK) cell-mediated cytotoxicity of human resting and activated human peripheral blood mononuclear cells (PBMC) was investigated. Addition of ergot alkaloid glycosides to the mixtures of effector and target cells potentiated the PBMC cytotoxicity against both NK-sensitive and -resistant target cells. The glycoconjugates of elymoclavine enhanced cytotoxicity of PBMC against NK-resistant target cells. The glycoconjugates of DH-lysergol potentiated NK cytotoxicity of PBMC against NK-sensitive target cells. PMID:8818236

Kren, V; Fiserová, A; Augé, C; Sedmera, P; Havlícek, V; Síma, P

1996-06-01

13

Immunomodulatory activity of Mollugo verticillata L.  

PubMed

This article describes the evaluation of immunomodulatory activity of Mollugo verticillata L. (Molluginaceae), a weed plant common in warm and/or wet regions of the American continent. Nitric oxide (NO) release was evaluated in mice peritoneal cell cultures treated in vivo using the ethanolic extract of M. verticillata with and without BCG. The plant extract showed immunostimulatory activity when peritoneal cells were stimulated in vitro with BCG antigen only. However, mice peritoneal cells treated with M. verticillata plus BCG showed a drastic reduction in NO production when they received the additional stimulus in vitro with BCG. Ethanolic extracts of M. verticillata could directly increase NO release by peritoneal cells, but suppress the immune response of these cells when treated with BCG antigen and Mycobacterium tuberculosis whole antigen (TB). Preliminary phytochemical tests allowed the detection of quercetin and triterpenoid glycosides in the ethanolic extract of M. verticillata, and those compounds are probably responsible for the effect of this plant material on the immune system. PMID:12725569

Ferreira, A P; Soares, G L G; Salgado, C A; Gonçalves, L S; Teixeira, F M; Teixeira, H C; Kaplan, M A C

2003-03-01

14

The immunomodulatory effects of the herbicide simazine on murine macrophage functions in vitro.  

PubMed

We examined the immunomodulating effects of simazine, a triazine herbicide, on murine peritoneal macrophages after in vitro pre-exposure. When thioglycollate-elicited macrophages pre-exposed to simazine were stimulated with lipopolysaccharide (LPS), the antitumor activity induced by LPS was suppressed by simazine. Simazine also inhibited poly I:C-induced antiviral activity and interferon (IFN) production in macrophages. In addition, the production of nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) which have been known to be major effector molecules in macrophage-mediated cytotoxicity was decreased by simazine pretreatment in a dose-dependent manner. However, simazine had little effect on phagocytosis and the level of hydrogen peroxide (H(2)O(2)), interleukin-1 (IL-1) and IL-6 by LPS-stimulated macrophages. Taken together, these data indicate that simazine has a differential immunomodulating effect on macrophage secretory and cellular activities. PMID:12206818

Kim, Kyung-Ran; Son, Eun-Wha; Rhee, Dong-Kwon; Pyo, Suhkneung

2002-10-01

15

A comparative study on immunomodulatory activity of polysaccharides from two official species of ganoderma (lingzhi).  

PubMed

Two Ganoderma species, G. lucidum and G. sinense, are listed as Lingzhi in Chinese Pharmacopoeia and they are considered to have the same therapeutic effects. Polysaccharides were the main immunomodulatory and anticancer components in Ganoderma. In this study, the chemical characters and the effects of polysaccharides from G. lucidum (GLPS) and G. sinense (GSPS) on macrophage functions were investigated and compared. Chemical studies showed that GLPS and GSPS were different, displaying various molecular weight distribution and ratio of monosaccharide components. In vitro pharmacological studies showed that both GLPS and GSPS had potent effects on macrophage functions, such as promoting macrophage phagocytosis, increasing their release of nitric oxide and cytokines interleukin (IL)-1?, IL-6, IL-10, and tumor necrosis factor-?. Generally, GLPS was more powerful than GSPS. This study is helpful to elucidate the active components and pharmacological variation between the 2 Ganoderma species. The structure-activity relationship of polysaccharides from Ganoderma needs further study. PMID:25204488

Meng, Lan-Zhen; Xie, Jing; Lv, Guang-Ping; Hu, De-Jun; Zhao, Jing; Duan, Jin-Ao; Li, Shao-Ping

2014-10-01

16

Immunomodulatory Activity of Xanthones from Calophyllum teysmannii var. inuphylloide.  

PubMed

Nine xanthones, including 3-(4-hydroxy-3-metnylbutyl)-4,8-dihydroxyxanthone, were isolated from the wood of a Thai collection of CALOPHYLLUM TEYSMANNII Miq. var. INUPHYLLOIDE (King) P. Stephen. Immunomodulatory activities of eight of these have been investigated. PMID:17260263

Gonzalez, M J; Nascimento, M S; Cidade, H M; Pinto, M M; Kijjoa, A; Anantachoke, C; Silva, A M; Herz, W

1999-05-01

17

Development of QSAR model for immunomodulatory activity of natural coumarinolignoids  

PubMed Central

Immunomodulation is the process of alteration in immune response due to foreign intrusion of molecules inside the body. Along with the available drugs, a large number of herbal drugs are promoted in traditional Indian treatments, for their immunomodulating activity. Natural coumarinolignoids isolated from the seeds of Cleome viscose have been recognized as having hepatoprotective action and have recently been tested preclinically for their immunomodulatory activity affecting both cell-mediated and humoral immune response. To explore the immunomodulatory compound from derivatives of coumarinolignoids, a quantitative structure activity relationship (QSAR) and molecular docking studies were performed. Theoretical results are in accord with the in vivo experimental data studied on Swiss albino mice. Immunostimulatory activity was predicted through QSAR model, developed by forward feed multiple linear regression method with leave-one-out approach. Relationship correlating measure of QSAR model was 99% (R2 = 0.99) and predictive accuracy was 96% (RCV2 = 0.96). QSAR studies indicate that dipole moment, steric energy, amide group count, lambda max (UV-visible), and molar refractivity correlates well with biological activity, while decrease in dipole moment, steric energy, and molar refractivity has negative correlation. Docking studies also showed strong binding affinity to immunomodulatory receptors. PMID:20856844

Yadav, Dharmendra K; Meena, Abha; Srivastava, Ankit; Chanda, D; Khan, Feroz; Chattopadhyay, SK

2010-01-01

18

Isolation and characterization of exopolysaccharide with immunomodulatory activity from fermentation broth of Morchella conica  

PubMed Central

Background and the purpose of this study Mushroom polysaccharides have traditionally been used for the prevention and treatment of a multitude of disorders like infectious illnesses, cancers and various autoimmune diseases. In vitro and in vivo studies suggest that certain polysaccharides affect immune system function. Morchella conica (M. conica) is a species of rare edible mushroom whose multiple medicinal functions have been proven. Thus, the objective of this study is to isolate and characterize of exopolysaccharide from submerged mycelial culture of M. conica, and to evaluate its immunomodulatory activity. Methods A water-soluble Morchella conica Polysaccharides (MCP) were extracted and isolated from the fermentation broth of M. conica through a combination of DEAE-cellulose and Sephacryl S-300 HR chromatograph. NMR and IR spectroscopy has played a developing role in identification of polysaccharide with different structure and composition from fungal and plant sources, as well as complex glycosaminoglycans of animal origin. Thus, NMR and IR spectroscopy were used to analyze the chemical structure and composition of the isolated polysaccharide. Moreover, the polysaccharide was tested for its immunomodulatory activity at different concentrations using in vitro model. Results The results showed that MCP may significantly modulate nitric oxide production in macrophages, and promote splenocytes proliferation. Analysis from HPLC, infrared spectra and nuclear magnetic resonance spectroscopy showed that MCP was a homogeneous mannan with an average molecular weight of approximately 81.2 kDa. The glycosidic bond links is ?6)-?-D-Man p-(1?. Conclusion The results suggested that the extracted MCP may modulate nitric oxide production in macrophages and promote splenocytes proliferation, and it may act as a potent immunomodulatory agent. PMID:23351529

2013-01-01

19

Immunomodulatory Activity in Vitro and in Vivo of Verbascose from Mung Beans (Phaseolus aureus).  

PubMed

In the present study, the immunostimulatory activity of verbascose from mung beans (Phaseolus aureus) was evaluated by using in vitro cell models and in vivo animal models. The results of in vitro experiments showed that verbascose could enhance the ability of devouring neutral red of peritoneal macrophages and promote the release of nitric oxide and immune reactive molecules such as interleukin (IL)-6, IL-1?, interferon (IFN)-?, and IFN-?. Treatment with verbascose at a dose of 200 ?g/mL exhibited the best effects. For assay in vivo, administration of verbascose at a medium dose of 90 mg/kg body weight could significantly increase the index of spleen, activity of lysozyme in spleen and serum, hemolysin level in serum, and swelling rate of earlap in the delayed type of hypersensitivity (DTH) of immunosuppressed mice. All of the results suggested that verbascose had potent immunostimulatory activity and could be explored as a potential natural immunomodulatory agent in functional foods. PMID:25317918

Dai, Zhuqing; Su, Di; Zhang, Yun; Sun, Yi; Hu, Bing; Ye, Hong; Jabbar, Saqib; Zeng, Xiaoxiong

2014-11-01

20

Chemistry and immunomodulatory activity of frankincense oil.  

PubMed

The yield of steam distillation of frankincense essential oil (3%); and its physicochemical constants were determined. Capillary GC/MS technique was used for the analysis of the oil. Several oil components were identified based upon comparison of their mass spectral data with those of reference compounds published in literature or stored in a computer library. The oil was found to contain monoterpenes (13.1%), sesquiterpenes (1%), and diterpenes (42.5%). The major components of the oil were duva-3,9,13-trien-1,5alpha-diol-1-acetate (21.4%), octyl acetate (13.4%), o-methyl anisole (7.6%), naphthalene decahydro-1,1,4a-trimethyl-6-methylene-5-(3-methyl-2-pentenyl) (5.7%), thunbergol (4.1%), phenanthrene-7-ethenyl-1,2,3,4,4a,5,6,7,8,9,10,10a-dodecahydro-1,1,4a,7-tetramethyl (4.1%), alpha-pinene (3.1%), sclarene (2.9%), 9-cis-retinal (2.8%), octyl formate (1.4%), verticiol (1.2%) decyl acetate (1.2%), n-octanol (1.1%). The chemical profile of the oil is considered as a chemotaxonomical marker that confirmed the botanical and geographical source of the resin. Biologically, the oil exhibited a strong immunostimulant activity (90% lymphocyte transformation) when assessed by a lymphocyte proliferation assay. PMID:12710734

Mikhaeil, Botros R; Maatooq, Galal T; Badria, Farid A; Amer, Mohamed M A

2003-01-01

21

Macrophages in malignant pleural effusions - alternatively activated tumor associated macrophages  

PubMed Central

Pleural macrophages are involved in local defense mechanisms against environmental pollution, bacteria and cancer. Their main function encompasses phagocytosis of degenerated mesothelial cells. In human pleural effusions macrophages represent more than half of all cells. A model of polarized macrophage activation (M1 and M2) was proposed, which defines a functionally different macrophage populations generated in response to various factors present in the inflamed environment. Tumor associated macrophages are a major component of the inflammatory infiltrate of most cancers. They can promote the proliferation and spread of cancer cells in the early stages of carcinogenesis and during metastasis. Macrophages isolated from malignant pleural effusions as well as tumor associated macrophages exhibit weak cytotoxic activity against tumor cells, increase their proliferative activity and may protect tumor cells from apoptosis. Defining biology of macrophages present in specific environment of the pleural effusion could allow the introduction of innovative diagnostic and therapeutic strategies. PMID:23788895

Sikora, Jan

2012-01-01

22

Immunomodulatory activity of polysaccharides isolated from Clerodendrum splendens: Beneficial effects in experimental autoimmune encephalomyelitis  

PubMed Central

Background Extracts of leaves from Clerodendrum have been used for centuries to treat a variety of medicinal problems in tropical Africa. However, little is known about the high-molecular weight active components conferring therapeutic properties to these extracts. Methods Polysaccharides from the leaves of Clerodendrum splendens were extracted and fractionated by ion exchange and size-exclusion chromatography. Molecular weight determination, sugar analysis, degree of methyl esterification, and other chemical characterization of the fractions were performed. Immunomodulatory activity of the fractions was evaluated by determining their ability to induce monocyte/macrophage nitric oxide (NO), cytokine production, and mitogen-activated protein kinase (MAPK) phosphorylation. Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice, and severity of EAE was monitored in mice treated with intraperitoneal (i.p.) injections of the most active polysaccharide fraction. Lymph nodes (LN) and spleen were harvested, and levels of cytokines in supernatants from LN cells and splenocytes challenged with myelin oligodendrocyte glycoprotein peptide were determined. Results Fractions containing type II arabinogalactan had potent immunomodulatory activity. Specifically, the high-molecular weight sub-fraction CSP-AU1 (average of 38.5 kDa) induced NO and cytokine [interleukin (IL)-1?, -1?, -6, -10, tumor necrosis factor (TNF; designated previously as TNF-?), and granulocyte macrophage-colony stimulating factor (GM-CSF)] production by human peripheral blood mononuclear cells (PBMCs) and monocyte/macrophages. CSP-AU1-induced secretion of TNF was prevented by Toll-like receptor 4 (TLR4) antagonist LPS-RS, indicating a role for TLR4 signaling. Treatment with CSP-AU1 also induced phosphorylation of a number of MAPKs in human PBMC and activated AP-1/NF-?B. In vivo treatment of mice with CSP-AU1 and CSP-NU1 resulted in increased serum IL-6, IL-10, TNF, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1?/CCL3, and MIP-1?/CCL4. CSP-AU1 treatment of mice with EAE (50 mg/kg, i.p., daily, 13 days) resulted in significantly reduced disease severity in this experimental model of multiple sclerosis. Levels of IL-13, TNF, interferon (IFN)-?, IL-17, and GM-CSF were also significantly decreased, whereas transforming growth factor (TGF)-? was increased in LN cells from CSP-AU1-treated EAE mice. Conclusions Polysaccharide CSP-AU1 is a potent natural innate immunomodulator with a broad spectrum of agonist activity in vitro and immunosupressive properties after chronic administration in vivo. PMID:23806004

2013-01-01

23

In vitro and in vivo immunomodulatory activity of sulfated polysaccharides from red seaweed Nemalion helminthoides.  

PubMed

Water-soluble sulfated polysaccharides from the red seaweed Nemalion helminthoides: two xylomannan fractions (N3 and N4) and a mannan fraction (N6) were investigated to determine their in vitro and in vivo immunomodulatory activities. N3 and N4 induced in vitro proliferation of macrophages of the murine cell line RAW 264.7 and significantly stimulated the production of nitric oxide (NO) and cytokines (IL-6 and TNF-?) in the same cells, whereas this response was not observed with the mannan N6. The cytokine production was also stimulated by sulfated xylomannans in vivo in BALB/c mice inoculated intravenously with these polysaccharides. Remarkably, when mice were treated with N3 and N4 for 1 h before being infected with Herpes simplex virus type 2, they remained asymptomatic with no signs of disease. The in vitro and in vivo results suggest that sulfated xylomannans could be strong immunomodulators. PMID:24444887

Pérez-Recalde, Mercedes; Matulewicz, María C; Pujol, Carlos A; Carlucci, María J

2014-02-01

24

Immunomodulatory activity of ouabain in Leishmania leishmania amazonensis-infected Swiss mice.  

PubMed

Ouabain is a cardiotonic steroid identified as an endogenous substance of human plasma, being produced by the adrenal, pituitary, and hypothalamus. Despite the studies demonstrating the ability of ouabain to modulate inflammation and other aspects of the immune response, the effects of this substance in Leishmaniasis is unknown. The purpose of this work was to understand the immunomodulatory activity of ouabain in experimental Leishmaniasis in Swiss mice. It was demonstrated that ouabain reduced total cell numbers in the peritoneal cavity as a reflex of the inhibition of neutrophil migration induced by Leishmania (L.) Amazonensis. Furthermore, ouabain reduced TNF-? and IFN-? levels, without cytotoxicity against peritoneal macrophages. These data showed the anti-inflammatory role of ouabain in the early events of the immune response triggered by Leishmania (L.) Amazonensis infection in murine model. PMID:23052777

Jacob, P L; Leite, J A; Alves, A K A; Rodrigues, Y K S; Amorim, F M; Néris, P L N; Oliveira, M R; Rodrigues-Mascarenhas, S

2013-03-01

25

Alternative macrophage activation and metabolism.  

PubMed

Obesity and its attendant metabolic disorders represent the great public health challenge of our time. Recent evidence suggests that onset of inflammation in metabolic tissues pathogenically links obesity to insulin resistance and type 2 diabetes. In this review, we briefly summarize the extant literature, paying special attention to the central role of the tissue-associated macrophage in the initiation of metabolic inflammation. We argue that rather than representing simple inflammatory disease, obesity and metabolic syndrome represent derangements in macrophage activation with concomitant loss of metabolic coordination. As such, the sequelae of obesity are as much products of the loss of positive macrophage influences as they are of the presence of deleterious inflammation. The therapeutic implications of this conclusion are profound because they suggest that pharmacologic targeting of macrophage activation, rather than simply inflammation, might be efficacious in treating this global epidemic. PMID:21034223

Odegaard, Justin I; Chawla, Ajay

2011-01-01

26

Purification, preliminary characterization and in vitro immunomodulatory activity of tiger lily polysaccharide.  

PubMed

A water-soluble polysaccharide (LLPS) from tiger lily was extracted by ultrasonic wave-assisted extraction. The LLPS, which was isolated by alcohol precipitation, was further purified by DEAE Sepharose Fast Flow and Sephadex G-100 chromatography, which resulted in LLPS fractions in LLPS-1, LLPS-2 and LLPS-3, with molecular weights of 350.5, 403.3 and 146.2kDa, respectively. LLPS-1 and LLPS-2 primarily consisted of glucose and mannose in a molar ratio of nearly 1:2 and 1:1, respectively. In contrast, LLPS-3 was primarily composed of arabinose, galactose, glucose and mannose in a molar ratio of nearly 2:2:2:1. LLPS fractions could stimulate the proliferation of macrophages. The in vitro immunomodulatory activity of the fractions was evaluated. The results showed that treatment with 25-400 ?g/mL of LLPS fractions could increase phagocytic activity and nitric oxide production of macrophages in a dose-dependent manner. PMID:24721071

Chen, Zhi-Gang; Zhang, Dan-Ni; Zhu, Qu; Yang, Qiu-Huizi; Han, Yong-Bin

2014-06-15

27

Immunomodulatory activities of Punarnavine, an alkaloid from Boerhaavia diffusa.  

PubMed

The effect of Punarnavine on the immune system was studied using Balb/c mice. Intraperitoneal administration of Punarnavine (40 mg/kg body weight) was found to enhance the total WBC count on 6(th) day. Bone marrow cellularity and number of alpha-esterase positive cells were also increased by the administration of Punarnavine. Treatment of Punarnavine along with the antigen, sheep red blood cells (SRBC), produced an enhancement in the circulating antibody titer and the number of plaque forming cells (PFC) in the spleen. Maximum number of PFC was obtained on the 6(th) day. Punarnavine also showed enhanced proliferation of splenocytes, thymocytes and bone marrow cells both in the presence and absence of specific mitogens in vitro and in vivo. More over administration of Punarnavine significantly reduced the LPS induced elevated levels of proinflammatory cytokines such as TNF-alpha, IL-1beta, and IL-6 in mice. These results indicate the immunomodulatory activity of Punarnavine. PMID:19555203

Manu, Kanjoormana Aryan; Kuttan, Girija

2009-01-01

28

Immunomodulatory and antitumor activities of a polysaccharide-peptide complex from a mycelial culture of Tricholoma sp., a local edible mushroom  

Microsoft Academic Search

A polysaccharide-peptide complex (PSPC) with immunomodulatory and antitumor activities was obtained from a submerged mycelial culture of Tricholoma sp., a local edible mushroom. The polysaccharide-peptide complex exhibited a molecular weight of 17 K in gel filtration and a single band after SDS-polyacrylamide gel electrophoresis. It was characterized by non-adsorption on both DEAE-Sepharose CL-6B and CM-cellulose. It could activate the macrophages,

H. X Wang; W. K Liu; T. B Ng; V. E. C Ooi; S. T Chang

1995-01-01

29

Macrophage immunomodulatory activity of polysaccharides isolated from Opuntia polyacantha  

Microsoft Academic Search

Opuntia polyacantha (prickly pear cactus) has been used extensively for its nutritional properties; however, less is known regarding medicinal properties of Opuntia tissues. In the present study, we extracted polysaccharides from O. polyacantha and used size-exclusion chromatography to fractionate the crude polysaccharides into four polysaccharide fractions (designated as Opuntia polysaccharides C-I to C-IV). The average Mr of fractions C-I through

Igor A. Schepetkin; Gang Xie; Liliya N. Kirpotina; Robyn A. Klein; Mark A. Jutila; Mark T. Quinn

2008-01-01

30

Structure and Antitumor and Immunomodulatory Activities of a Water-Soluble Polysaccharide from Dimocarpus longan Pulp  

PubMed Central

A new water-soluble polysaccharide (longan polysaccharide 1 (LP1)) was extracted and successfully purified from Dimocarpus longan pulp via diethylaminoethyl (DEAE)-cellulose anion-exchange and Sephacryl S-300 HR gel chromatography. The chemical structure was determined using Infrared (IR), gas chromatography (GC) and nuclear magnetic resonance (NMR) analysis. The results indicated that the molecular weight of the sample was 1.1 × 105 Da. Monosaccharide composition analysis revealed that LP1 was composed of Glc, GalA, Ara and Gal in a molar ratio of 5.39:1.04:0.74:0.21. Structural analysis indicated that LP1 consisted of a backbone of ?4)-?-d-Glcp-(1?4)-?-d-GalpA-(1?4)-?-d-Glcp-(1?4)-?-d-Glcp-(1? units with poly saccharide side chains composed of ?2)-?-d-Fruf-(1?2)-l-sorbose-(1? attached to the O-6 position of the ?-d-Glcp residues. In vitro experiments indicated that LP1 had significantly high antitumor activity against SKOV3 and HO8910 tumor cells, with inhibition percentages of 40% and 50%, respectively. In addition, LP1 significantly stimulated the production of the cytokine interferon-? (IFN-?), increased the activity of murine macrophages and enhanced B- and T-lymphocyte proliferation. The results of this study demonstrate that LP1 has potential applications as a natural antitumor agent with immunomodulatory activity. PMID:24663085

Meng, Fa-Yan; Ning, Yuan-Ling; Qi, Jia; He, Zhou; Jie, Jiang; Lin, Juan-Juan; Huang, Yan-Jun; Li, Fu-Sen; Li, Xue-Hua

2014-01-01

31

Immunomodulatory Activity of Acidic Polysaccharides Isolated from Tanacetum vulgare L  

PubMed Central

Tanacetum vulgare L. (Tansy) has been extensively used in folk medicine for treatment of a variety of medical disorders. In the present study, we isolated and purified four acidic polysaccharide fractions (designated T-I to T-IV) from Tansy florets by the sequential use of hot-water extraction, ethanol precipitation, ultra-filtration, anion-exchange, and size-exclusion chromatography. The average Mr of fractions T-I through T-IV was estimated to be 326, 151, 64 and 9 kDa, respectively, as determined by high performance size-exclusion chromatography analysis. Sugar composition analysis revealed that Tansy polysaccharides consisted primarily of galacturonic acid, galactose, arabinose, and rhamnose. Fractions T-II through T-IV contained an arabinogalactan type II structure, as determined by reaction with Yariv reagent. High Mr fractions T-I and T-II exhibited potent macrophage/monocyte-activating activity, enhancing production of reactive oxygen species (ROS), nitric oxide (NO), and tumor necrosis factor ? (TNF-?) by J774.A1 murine macrophages, and activating nuclear factor ?B (NF-?B) in THP-1 human monocytes. In addition, Tansy polysaccharides stimulated human neutrophil function by greatly enhancing neutrophil myeloperoxidase (MPO) release. Furthermore, the low Mr fraction T-IV had potent complement-fixing activity, which may also contribute to the anti-inflammatory and would-healing properties of Tansy extracts. Taken together, our results provide a molecular basis to explain at least part of the beneficial therapeutic effects of Tansy extracts, and support the concept of using Tansy polysaccharides as an immunotherapeutic adjuvant. PMID:17996673

Xie, Gang; Schepetkin, Igor A.; Quinn, Mark T.

2008-01-01

32

Immunomodulatory activity of acidic polysaccharides isolated from Tanacetum vulgare L.  

PubMed

Tanacetum vulgare L. (Tansy) has been extensively used in folk medicine for treatment of a variety of medical disorders. In the present study, we isolated and purified four acidic polysaccharide fractions (designated T-I to T-IV) from Tansy florets by the sequential use of hot-water extraction, ethanol precipitation, ultra-filtration, anion-exchange, and size-exclusion chromatography. The average M(r) of fractions T-I through T-IV was estimated to be 326, 151, 64 and 9 kDa, respectively, as determined by high performance size-exclusion chromatography analysis. Sugar composition analysis revealed that Tansy polysaccharides consisted primarily of galacturonic acid, galactose, arabinose, and rhamnose. Fractions T-II through T-IV contained an arabinogalactan type II structure, as determined by reaction with Yariv reagent. High M(r) fractions T-I and T-II exhibited potent macrophage/monocyte-activating activity, enhancing production of reactive oxygen species (ROS), nitric oxide (NO), and tumor necrosis factor alpha (TNF-alpha) by J774.A1 murine macrophages, and activating nuclear factor kappaB (NF-kappaB) in THP-1 human monocytes. In addition, Tansy polysaccharides stimulated human neutrophil function by greatly enhancing neutrophil myeloperoxidase (MPO) release. Furthermore, the low M(r) fraction T-IV had potent complement-fixing activity, which may also contribute to the anti-inflammatory and would-healing properties of Tansy extracts. Taken together, our results provide a molecular basis to explain at least part of the beneficial therapeutic effects of Tansy extracts, and support the concept of using Tansy polysaccharides as an immunotherapeutic adjuvant. PMID:17996673

Xie, Gang; Schepetkin, Igor A; Quinn, Mark T

2007-12-15

33

Macrophage activation by endogenous danger signals  

PubMed Central

Macrophages are cells that function as a first line of defence against invading microorganisms. One of the hallmarks of macrophages is their ability to become activated in response to exogenous ‘danger signals’. Most microbes have molecular patterns (PAMPS) that are recognized by macrophages and trigger this activation response. There are many aspects of the activation response to PAMPS that are recapitulated when macrophages encounter endogenous danger signals. In response to damaged or stressed self, macrophages undergo physiological changes that include the initiation of signal transduction cascades from germline-encoded receptors, resulting in the elaboration of chemokines, cytokines and toxic mediators. This response to endogenous mediators can enhance inflammation, and thereby contribute to autoimmune pathologies. Often the overall inflammatory response is the result of cooperative activation signals from both exogenous and endogenous signals. Macrophage activation plays a critical role, not only in the initiation of the inflammatory response but also in the resolution of this response. The clearance of granulocytes and the elaboration of anti-inflammatory mediators by macrophages contribute to the dissolution of the inflammatory response. Thus, macrophages are a key player in the initiation, propagation and resolution of inflammation. This review summarizes our understanding of the role of macrophages in inflammation. We pay particular attention to the endogenous danger signals that macrophages may encounter and the responses that these signals induce. The molecular mechanisms responsible for these responses and the diseases that result from inappropriately controlled macrophage activation are also examined. PMID:18161744

Zhang, X; Mosser, DM

2008-01-01

34

Lactobacillus acidophilus L-92 Cells Activate Expression of Immunomodulatory Genes in THP-1 Cells  

PubMed Central

To understand the immunomodulatory effects of Lactobacillus acidophilus L-92 cells suggested from our previous study of in vivo anti-allergy and anti-virus effects, host immune responses in macrophage-like THP-1 cells after 4?h (the early phase) and 24?h (the late phase) of cocultivation with L-92 cells were investigated by transcriptome analysis. In the early phase of L-92 treatment, various transcription regulator genes, such as, NFkB1, NFkB2, JUN, HIVEP2 and RELB, and genes encoding chemokines and cytokines, such as CCL4, CXCL11, CCL3 and TNF, were upregulated. Two transmembrane receptor genes, TLR7 and ICAM1, were also upregulated in the early phase of treatment. In contrast, many transmembrane receptor genes, such as IL7R, CD80, CRLF2, CD86, CD5, HLA-DQA1, IL2RA, IL15RA and CSF2RA, and some cytokine genes, including IL6, IL23A and CCL22, were significantly upregulated in the late phase after L-92 exposure. Some genes encoding cytokines, such as IL1A, IL1B and IL8, and the enzyme IDO1 were upregulated at both the early and the late phases of treatment. These results suggest that probiotic L-92 might promote Th1 and regulatory T-cell responses by activation of the MAPK signaling pathway, followed by the NOD-like receptor signaling pathway in THP-1 cells. PMID:25379363

YANAGIHARA, Sae; GOTO, Hiroaki; HIROTA, Tatsuhiko; FUKUDA, Shinji; OHNO, Hiroshi; YAMAMOTO, Naoyuki

2014-01-01

35

Immunomodulatory activity of red ginseng against influenza A virus infection.  

PubMed

Ginseng herbal medicine has been known to have beneficial effects on improving human health. We investigated whether red ginseng extract (RGE) has preventive effects on influenza A virus infection in vivo and in vitro. RGE was found to improve survival of human lung epithelial cells upon influenza virus infection. Also, RGE treatment reduced the expression of pro-inflammatory genes (IL-6, IL-8) probably in part through interference with the formation of reactive oxygen species by influenza A virus infection. Long-term oral administration of mice with RGE showed multiple immunomodulatory effects such as stimulating antiviral cytokine IFN-? production after influenza A virus infection. In addition, RGE administration in mice inhibited the infiltration of inflammatory cells into the bronchial lumens. Therefore, RGE might have the potential beneficial effects on preventing influenza A virus infections via its multiple immunomodulatory functions. PMID:24473234

Lee, Jong Seok; Hwang, Hye Suk; Ko, Eun-Ju; Lee, Yu-Na; Kwon, Young-Man; Kim, Min-Chul; Kang, Sang-Moo

2014-01-01

36

Immunomodulatory Activity of Red Ginseng against Influenza A Virus Infection  

PubMed Central

Ginseng herbal medicine has been known to have beneficial effects on improving human health. We investigated whether red ginseng extract (RGE) has preventive effects on influenza A virus infection in vivo and in vitro. RGE was found to improve survival of human lung epithelial cells upon influenza virus infection. Also, RGE treatment reduced the expression of pro-inflammatory genes (IL-6, IL-8) probably in part through interference with the formation of reactive oxygen species by influenza A virus infection. Long-term oral administration of mice with RGE showed multiple immunomodulatory effects such as stimulating antiviral cytokine IFN-? production after influenza A virus infection. In addition, RGE administration in mice inhibited the infiltration of inflammatory cells into the bronchial lumens. Therefore, RGE might have the potential beneficial effects on preventing influenza A virus infections via its multiple immunomodulatory functions. PMID:24473234

Lee, Jong Seok; Hwang, Hye Suk; Ko, Eun-Ju; Lee, Yu-Na; Kwon, Young-Man; Kim, Min-Chul; Kang, Sang-Moo

2014-01-01

37

QSAR and Docking Studies on Capsazepine Derivatives for Immunomodulatory and Anti-Inflammatory Activity  

PubMed Central

Capsazepine, an antagonist of capsaicin, is discovered by the structure and activity relationship. In previous studies it has been found that capsazepine has potency for immunomodulation and anti-inflammatory activity and emerging as a favourable target in quest for efficacious and safe anti-inflammatory drug. Thus, a 2D quantitative structural activity relationship (QSAR) model against target tumor necrosis factor-? (TNF-?) was developed using multiple linear regression method (MLR) with good internal prediction (r2?=?0.8779) and external prediction (r2pred?=?0.5865) using Discovery Studio v3.5 (Accelrys, USA). The predicted activity was further validated by in vitro experiment. Capsazepine was tested in lipopolysaccharide (LPS) induced inflammation in peritoneal mouse macrophages. Anti-inflammatory profile of capsazepine was assessed by its potency to inhibit the production of inflammatory mediator TNF-?. The in vitro experiment indicated that capsazepine is an efficient anti-inflammatory agent. Since, the developed QSAR model showed significant correlations between chemical structure and anti-inflammatory activity, it was successfully applied in the screening of forty-four virtual derivatives of capsazepine, which finally afforded six potent derivatives, CPZ-29, CPZ-30, CPZ-33, CPZ-34, CPZ-35 and CPZ-36. To gain more insights into the molecular mechanism of action of capsazepine and its derivatives, molecular docking and in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) studies were performed. The results of QSAR, molecular docking, in silico ADMET screening and in vitro experimental studies provide guideline and mechanistic scope for the identification of more potent anti-inflammatory & immunomodulatory drug. PMID:25003344

Shukla, Aparna; Sharma, Pooja; Prakash, Om; Singh, Monika; Kalani, Komal; Khan, Feroz; Bawankule, Dnyaneshwar Umrao; Luqman, Suaib; Srivastava, Santosh Kumar

2014-01-01

38

Evaluation and characterization of the immunomodulatory activity of the protein extract from Citrullus colocynthis L  

Microsoft Academic Search

Citrullus colocynthis L. is a plant widely used in Moroccan traditional medicine as a strong laxative and has many others uses. The aim of the present work is to evaluate the immunomodulatory activity of the protein extract (PE) from seeds of C. colocynthis. The results of this study showed that the PE has an immunosuppressive activity in vitro. The activity

Abdeljlil Daoudi; Dalila Bousta; Lotfi Aarab; Essam Abdel-Sattar

2011-01-01

39

Molecular characterization and immunomodulatory activity of sulfated fucans from Agarum cribrosum.  

PubMed

The sulfated-fucans, known as fucoidans, were isolated from Agarum cribrosum and fractionated using ion-exchange chromatography to determine their molecular characteristics and in vitro immunomodulatory activity. The crude and fractionated fucoidans (F1 and F2) consisted mostly of carbohydrates (52.4-56.0%), sulfates (12.7-23.0%) and uronic acid (14.1-21.8%), with a small amount of proteins (3.9-9.3%), and included various levels of fucose (44.0-46.7%), mannose (18.9-26.8%), galactose (16.8-33.0%), xylose (10.7-17.0%) and glucose (3.5-9.5%). The crude and fractionated fucans contained one or two subfractions with average molecular weights (Mw) ranging from 110.1×10(3) to 2420×10(3)g/mol. The fractionated fucoidan, especially the F1 fraction, strongly stimulated murine macrophages (Raw 264.7 cells), producing a considerable amount of nitric oxide (NO) and inducing expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2) and interleukin-10 (IL-10) transcripts by activation of nuclear factor-kappa B (NF-?B) and mitogen-activated protein kinases (MAPKs) pathways. The maximally immunoenhancing F1 fraction was mainly composed of (1?3)-linked fucose, (1?2)-linked mannose and (1?4)-linked glucuronic acid with sulfates at C-2 or both the C-2 and C-4 positions in (1?2,3)- and (1?2,3,4)-linked fucose residues. PMID:25256513

Cho, MyoungLae; Lee, Dong-Jin; Kim, Jin-Kyung; You, SangGuan

2014-11-26

40

Inhibition of inflammatory mediators by neobavaisoflavone in activated RAW264.7 macrophages.  

PubMed

Flavonoids and coumarins are the major bioactive constituents identified in Psoralea corylifolia. The active fraction isolated from fruits, seeds and roots possesses antibacterial, antioxidative and immunomodulatory properties. Neobavaisoflavone is one of the flavonoids found in Psoralea corylifolia. In the present study we investigated in vitro the anti-inflammatory activity of neobavaisoflavone. Macrophages play an important role in inflammation through the release of inflammatory mediators involved in the immune response. Inappropriate and prolonged macrophage activation is largely responsible for the pathology of acute and chronic inflammatory conditions. Neobavaisoflavone significantly inhibited the production of reactive oxygen species (ROS), reactive nitrogen species (RNS) and cytokines: IL-1?, IL-6, IL-12p40, IL-12p70, TNF-? in LPS+IFN-?- or PMA- stimulated RAW264.7 macrophages. PMID:21540797

Szliszka, Ewelina; Skaba, Dariusz; Czuba, Zenon P; Krol, Wojciech

2011-01-01

41

SECRETION OF PLASMINOGEN ACTIVATOR BY STIMULATED MACROPHAGES  

PubMed Central

Cultured thioglycollate-stimulated peritoneal macrophages synthesize, accumulate, and continuously release high levels of plasminogen activators for at least 4 days whereas cultures of unstimulated macrophages do not; the higher specific catalytic activity of released vs. cell-associated enzyme suggests that the plasminogen activators are actively secreted. The major macrophage plasminogen activator is a serine protease of mol wt 48,000, and thus resembles the comparable enzyme released by virally transformed fibroblasts. Macrophages release a second plasminogen activator of mol wt 28,000 that is also a serine enzyme. The secretion products released by stimulated and unstimulated macrophages have been compared by SDS-polyacrylamide gel electrophoresis after chemical labeling with 3H-DFP or biosynthetic labeling with 14C-amino acids. These procedures show that some proteins are formed in both cultures, whereas others are uniquely secreted by each type of macrophage. The serine enzymes released by the two kinds of macrophages differ in specificity and electrophoretic mobility. PMID:4816302

Unkeless, Jay C.; Gordon, Saimon; Reich, E.

1974-01-01

42

Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects  

Microsoft Academic Search

The anti-tumour effects of thalidomide have been associated with its anti-angiogenic properties. Second generation thalidomide analogues are distinct compounds with enhanced therapeutic potential. Although these compounds are beginning to enter trials for the treatment of cancer there is very little information regarding the anti-angiogenic activity of these clinically relevant compounds. Furthermore, it is not known how the various immunomodulatory activities

K Dredge; J B Marriott; C D Macdonald; H-W Man; R Chen; G W Muller; D Stirling; A G Dalgleish

2002-01-01

43

Activated Macrophage Survival Is Coordinated by TAK1 Binding Proteins  

PubMed Central

Macrophages play diverse roles in tissue homeostasis and immunity, and canonically activated macrophages are critically associated with acute inflammatory responses. It is known that activated macrophages undergo cell death after transient activation in some settings, and the viability of macrophages impacts on inflammatory status. Here we report that TGF?- activated kinase (TAK1) activators, TAK1-binding protein 1 (TAB1) and TAK1-binding protein 2 (TAB2), are critical molecules in the regulation of activated macrophage survival. While deletion of Tak1 induced cell death in bone marrow derived macrophages even without activation, Tab1 or Tab2 deletion alone did not profoundly affect survival of naïve macrophages. However, in lipopolysaccharide (LPS)-activated macrophages, even single deletion of Tab1 or Tab2 resulted in macrophage death with both necrotic and apoptotic features. We show that TAB1 and TAB2 were redundantly involved in LPS-induced TAK1 activation in macrophages. These results demonstrate that TAK1 activity is the key to activated macrophage survival. Finally, in an in vivo setting, Tab1 deficiency impaired increase of peritoneal macrophages upon LPS challenge, suggesting that TAK1 complex regulation of macrophages may participate in in vivo macrophage homeostasis. Our results demonstrate that TAB1 and TAB2 are required for activated macrophages, making TAB1 and TAB2 effective targets to control inflammation by modulating macrophage survival. PMID:24736749

Mihaly, September R.; Morioka, Sho; Ninomiya-Tsuji, Jun; Takaesu, Giichi

2014-01-01

44

Antinociceptive, Immunomodulatory and Antipyretic Activity of Nymphayol Isolated from Nymphaea stellata (Willd.) Flowers  

PubMed Central

In the present study, we aimed to analyze the antinociceptive, immunomodulatory and antipyretic activities of nymphayol were investigated in wistar rats and mice. Antinociceptive effect was evaluated by acetic acid induced writhing, formalin induced paw licking and hot-plate tests. Immunomodulatory activity was assessed by neutrophil adhesion test, humoral response to sheep red blood cells, delayed-type hypersensitivity, phagocytic activity and cyclophosphamide induced myelosuppression. Antipyretic activity was evaluated by yeast induced hyperthermia in rats. Nymphayol produced signifi cant (p<0.05) antinociceptive activity in acetic acid induced writhing response and late phase of the formalin induced paw licking response. Pre-treatment with nymphayol (50 mg/kg, oral) evoked a signifi cant increase in neutrophil adhesion to nylon fi bres. The augmentation of humoral immune response to sheep red blood cells by nymphayol (50 mg/kg) was evidenced by increase in antibody titres in rats. Oral administration of nymphayol (50 mg/kg) to rats potentiated the delayed-type hypersensitivity reaction induced by sheep red blood cells. Treatment with nymphayol showed a signifi cant (p<0.05) reduction in pyrexia in rats. The results suggest that nymphayol possesses potent anti-nociceptive, immunomodulatory and antipyretic activities. PMID:24244827

Pandurangan, Subash-Babu; Paul, Antony Samy; Savarimuthu, Ignacimuthu; Ali, Alshatwi A

2013-01-01

45

Immunomodulatory Activity of the Water Extract from Medicinal Mushroom Inonotus obliquus  

PubMed Central

The immunomodulatory effect of aqueous extract of Inonotus obliquus, called as Chaga, was tested on bone marrow cells from chemically immunosuppressed mice. The Chaga water extract was daily administered for 24 days to mice that had been treated with cyclophosphamide (400 mg/kg body weight), immunosuppressive alkylating agent. The number of colony-forming unit (CFU)-granulocytes/macrophages (GM) and erythroid burst-forming unit (BFU-E), increased almost to the levels seen in non-treated control as early as 8 days after treatment. Oral administration of the extract highly increased serum levels of IL-6. Also, the level of TNF-? was elevated by the chemical treatment in control mice, whereas was maintained at the background level in the extract-treated mice, indicating that the extract might effectively suppress TNF-? related pathologic conditions. These results strongly suggest the great potential of the aqueous extract from Inonotus obliquus as immune enhancer during chemotherapy. PMID:24049493

2005-01-01

46

Antigens associated with various cytotoxic activities of murine peripheral macrophages.  

PubMed

BCG- or glucan-elicited murine peripheral macrophages released a cytotoxin in the presence of loach egg lectin, whereas proteose peptone-, glycogen-, or thioglycollate-elicited or resident macrophages did not. The macrophages that released cytotoxin coincided with those that showed lectin-dependent macrophage-mediated cytolysis (LDMC) in response to loach egg lectin. The cytotoxin released by BCG-elicited macrophages in response to loach egg lectin had a molecular weight of 55 K daltons. The macrophages that released cytotoxin and other cytotoxic macrophages such as those that showed LDMC- and antibody-dependent macrophage-mediated cytolysis (ADMC) were examined by using several antibodies to surface antigens of macrophages. The results showed that murine peripheral macrophages could be divided into three types. Resident macrophages (Type I) which had common macrophage antigens (Mac-1 and B12) showed only LDMC in response to wheat germ agglutinin. Some elicited macrophages (Type II) were asialo GM1-positive and showed both ADMC and LDMC in response to wheat germ agglutinin. Activated macrophages (Type III) showed LDMC in response to loach egg lectin and cytotoxin-release, but had no antigen detectable with monoclonal anti-macrophage antibody (C14). These three types of macrophages were clearly distinguished diagrammatically by their roof-shaped, rocket-shaped and irregular-shaped profiles of activities and antigens. These data suggest that several selected surface antigens of macrophages are associated with distinct cytotoxic stages of peripheral macrophages. PMID:3540536

Okutomi, T; Satoh, M; Oshima, H; Yamazaki, M

1986-01-01

47

Enhancement of ATP generation capacity, antioxidant activity and immunomodulatory activities by Chinese Yang and Yin tonifying herbs  

PubMed Central

Chinese tonifying herbs such as Herba Cistanche, Ganoderma and Cordyceps, which possess antioxidant and/or immunomodulatory activities, can be useful in the prevention and treatment of age-related diseases. Pharmacological studies on Yang and Yin tonifying herbs suggest that Yang tonifying herbs stimulate mitochondrial adenosine triphosphate (ATP) generation, presumably through the intermediacy of reactive oxidant species, leading to the enhancement of cellular/mitochondrial antioxidant status. Yin tonifying herbs, however, apart from possessing antioxidant properties, exert mainly immunomodulatory functions that may boost a weak immune system and may also suppress overreactive immune responses. The abilities of Yang and Yin Chinese tonifying herbs to enhance ATP generation and to exhibit antioxidant and/or immunomodulatory actions are the pharmacological basis for their beneficial effects on the retardation of aging. PMID:17386115

Ko, Kam Ming; Leung, Hoi Yan

2007-01-01

48

Assessing for unique immunomodulatory and neuroplastic profiles of physical activity subtypes: a focus on psychiatric disorders.  

PubMed

Physical activity (PA) is emerging as a safe and effective tool in the prevention and treatment of psychiatric disorders. PA subtypes include aerobic, resistance, flexibility, neuromotor (involving balance, agility and co-ordination), mind-body (e.g. tai chi, qi gong and yoga) and mixed type trainings. Evidence from clinical trials suggests that PA subtypes can have positive clinical effects, however the effects on the symptomatology may vary according to the PA subtype. It therefore stands to reason that various PA subtypes may modulate the immune system and neuroplastic processes differently. This systematic review aims to assess the immunomodulatory and neuroplastic profiles of various PA subtypes, particularly in unipolar depression and age-related cognitive decline (ARCD). The literature suggests several unique immunomodulatory and neuroplastic profiles for PA subtypes (i.e. resistance, aerobic and mind-body) in depression and ARCD. In depression, levels of various cytokines at baseline may predict treatment response to subtypes of PA and pharmacological agents. The pro-neuroplastic effects of resistance and aerobic PA in ARCD may differ due to variances in neurotrophin profiles. At this stage of literature in the field, it is difficult to draw firm conclusions on the specific immunomodulatory and neuroplastic pathways involved in these PA subtypes given of the small number of comparative studies and methodological heterogeneity between studies (e.g. study population age and illness severity, as well as duration and intensity of PA intervention). This important field requires well-designed, high-quality comparative studies to better describe unique immunomodulatory and neuroplastic profiles. PMID:24269526

Eyre, Harris A; Baune, Bernhard T

2014-07-01

49

Brazilian Propolis Antileishmanial and Immunomodulatory Effects  

PubMed Central

The antileishmanial and immunomodulatory effects of propolis collected in Botucatu, São Paulo State, Brazil, were evaluated in Leishmania (Viannia) braziliensis experimental infection. The antileishmanial effect of propolis on promastigote forms was verified by reducing growth and by promoting morphologic alterations observed by scanning electron microscopy. In in vitro immunomodulatory assays, macrophages were pretreated with propolis and then infected with L. (V.) braziliensis. In vivo, supernatants from liver cells and peritoneal exudate of BALB/c mice pretreated with propolis and infected with Leishmania (107/mL promastigotes) were collected, and TNF-? and IL-12 were measured by ELISA. Macrophages incubated with propolis showed a significant increase in interiorization and further killing of parasites. An increased TNF-? production was seen in mice pretreated with propolis, whereas IL-12 was downregulated during the infection. In conclusion, Brazilian propolis showed a direct action on the parasite and displayed immunomodulatory effects on murine macrophages, even though the parasite has been reported to affect the activation pathways of the cell. The observed effects could be associated with the presence of phenolic compounds (flavonoids, aromatic acids, and benzopyranes), di- and triterpenes, and essential oils found in our propolis sample. PMID:23762152

da Silva, Suelen Santos; Thome, Graciele da Silva; Cataneo, Allan Henrique Depieri; Miranda, Milena Menegazzo; Felipe, Ionice; Andrade, Celia Guadalupe Tardeli de Jesus; Watanabe, Maria Angelica Ehara; Piana, Gilce Maria; Sforcin, Jose Mauricio; Pavanelli, Wander Rogerio; Conchon-Costa, Ivete

2013-01-01

50

Immunomodulatory activity of plant residues on ovine neutrophils.  

PubMed

Neutrophils play an essential role in host defense and inflammation. Plants have long been used to improve the immune function, but for most of them specific investigations on animal health are lacking. In the present study, water and hydroethanolic extracts from 11 plant wastes have been screened on immune responses of ovine neutrophils. Eight sheep clinically healthy, not lactating, non-pregnant were selected and used for the experiment. Freshly isolated neutrophils were incubated with the extracts of the residues at increasing doses, and then they were tested for adhesion and superoxide production induced with PMA. The residues of Larix decidua, Thymus vulgaris, Salix alba, Sinupret, Helianthus annuus, Mangifera indica modulated the neutrophil immune functions, moreover, Larix decidua, Thymus vulgaris and Salix alba presented the highest anti-inflammatory activity. PMID:18667240

Farinacci, Maura; Colitti, Monica; Sgorlon, Sandy; Stefanon, Bruno

2008-11-15

51

A Possible Molecular Mechanism of Immunomodulatory Activity of Bilirubin  

PubMed Central

Bilirubin is an endogenous product of heme degradation in mammals. Bilirubin has long been considered as a cytotoxic waste product that needs to be excreted. However, increasing evidence suggests that bilirubin possesses multiple biological activities. In particular, recent studies have shown that bilirubin should be a protective factor for several autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus. Since these autoimmune diseases are closely associated with specific types of human leukocyte antigens (HLAs), we have hypothesized that bilirubin might bind to the antigenic peptide-binding groove of the HLA molecules and exert its immunosuppressive actions. In order to evaluate the hypothesis, theoretical docking studies between bilirubin and the relevant HLA molecules have been undertaken. The in silico studies have clearly shown that bilirubin may bind to the antigenic peptide-binding groove of the HLA molecules relevant to the autoimmune diseases with significant affinity. The bound bilirubin may block the binding of antigenic peptides to be presented to T cell receptors and lead to suppression of the autoimmune responses. Based on this hypothesis new drug discovery research for autoimmune diseases will be conducted.

Isogai, Hideto

2013-01-01

52

Activation of Macrophages by Exopolysaccharide Produced by MK1 Bacterial Strain Isolated from Neungee Mushroom, Sarcodon aspratus  

PubMed Central

Background The MK1 strain, a novel bacterial isolate from soft-rotten tissue of the Neungee mushroom, produces copious amounts of exopolysaccharide (EPS) in a dextrose minimal medium. This study examined the molecular characteristics and immunomodulatory activity of MK1 EPS. Methods The EPS in the culture supernatant was purified by cold ethanol precipitation, and characterized by SDS-PAGE/silver staining and Bio-HPLC. The immunomodulatory activities of the EPS were examined using the mouse monocytic cell line, RAW 264.7 cells. Results The molecular weights of the purified EPS were rather heterogeneous, ranging from 10.6 to 55 kDa. The EPS was composed of glucose, rhamnose, mannose, galactose, and glucosamine at an approximate molar ratio of 1.00:0.8:0.71:0.29:0.21. EPS activated the RAW cells to produce cytokines, such as TNF-? and IL-1?, and nitric oxide (NO). EPS also induced the expression of co-stimulatory molecules, such as B7-1, B7-2 and ICAM-1, and increased the phagocytic activity. The macrophage-activating activity of EPS was not due to endotoxin contamination because the treatment of EPS with polymyin B did not reduce the macrophage-activating activity. Conclusion The EPS produced from the MK1 strain exerts macrophage-activating activity. PMID:21286384

Im, Sun-A; Wang, Wenxia; Lee, Chong-Kil

2010-01-01

53

Disruption of tissue plasminogen activator gene reduces macrophage migration  

E-print Network

Disruption of tissue plasminogen activator gene reduces macrophage migration Changchun Ling a,1 that disruption of tPA gene reduces macrophage migration after sciatic nerve injury in mice. Moreover, lack of tPA activity attenuates migrating ability of macrophages and affects MMP-9 expression and activity

54

Evaluation of in vitro anti-proliferative and immunomodulatory activities of compounds isolated from Curcuma longa.  

PubMed

The rhizome of Curcuma longa (CL) has been commonly used in Asia as a potential candidate for the treatment of different diseases, including inflammatory disorders and cancers. The present study evaluated the anti-proliferative activities of the isolated compounds (three curcuminoids and two turmerones) from CL, using human cancer cell lines HepG2, MCF-7 and MDA-MB-231. The immunomodulatory activities of turmerones (alpha and aromatic) isolated from CL were also examined using human peripheral blood mononuclear cells (PBMC). Our results showed that the curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) and alpha-turmerone significantly inhibited proliferation of cancer cells in dose-dependent manner. The IC(50) values of these compounds in cancer cells ranged from 11.0 to 41.8 microg/ml. alpha-Turmerone induced MDA-MB-231 cells to undergo apoptosis, which was confirmed by annexin-V and propidium iodide staining, and DNA fragmentation assay. The caspase cascade was activated as shown by a significant decrease of procaspases-3, -8 and -9 in alpha-turmerone treated cells. Both alpha-turmerone and aromatic-turmerone showed stimulatory effects on PBMC proliferation and cytokine production. The anti-proliferative effect of alpha-turmerone and immunomodulatory activities of ar-turmerone was shown for the first time. The findings revealed the potential use of CL crude extract (containing curcuminoids and volatile oil including turmerones) as chemopreventive agent. PMID:20438793

Yue, Grace G L; Chan, Ben C L; Hon, Po-Ming; Lee, Mavis Y H; Fung, Kwok-Pui; Leung, Ping-Chung; Lau, Clara B S

2010-01-01

55

Control of macrophage activation and function by PPARs  

PubMed Central

Macrophages, a key component of the innate defense against pathogens, participate in the initiation and resolution of inflammation, and in the maintenance of tissues. These diverse and at times antithetical functions of macrophages are executed via distinct activation states, ranging from classical to alternative to deactivation. Because the dysregulation of macrophage activation is pathogenically linked to various metabolic, inflammatory and immune disorders, regulatory proteins controlling macrophage activation have emerged as important new therapeutic targets. Here, the mechanisms by which Peroxisome Proliferator Activated Receptors (PPARs) transcriptionally regulate macrophage activation in health and disease states, including obesity, insulin resistance and cardiovascular disease, will be reviewed. PMID:20508200

Chawla, Ajay

2010-01-01

56

Brazilian green propolis: anti-inflammatory property by an immunomodulatory activity.  

PubMed

The immunomodulatory and anti-inflammatory activities of green propolis extracts from Apis mellifera were investigated using acute and chronic inflammation models. Swiss mice were anesthetized and a cotton pellet granuloma was implanted in subcutaneous tissue. Then the mice were divided into six groups and received apyrogenic water or different propolis extracts by oral route (5?mg/kg). According to the treatment the groups were designated as E1A, E1B, E10, E11, and E12. The control group received apyrogenic water. The treatment was performed by six days when the mice were killed. The blood and the bronchoalveolar lavage (BAL) were collected to measure the leukocyte recruitment. In acute pulmonary inflammation, Balb/c mice received lipopolysaccharide (LPS) of Escherichia coli by intranasal route for three days. Concomitantly the mice received by oral route apyrogenic water (control) or E10 and E11 propolis extracts. BAL was performed to assess the inflammatory infiltrate and cytokine quantification. The results showed that the E11 extract has anti-inflammatory property in both models by the inhibition of proinflammatory cytokines and increase of anti-inflammatory cytokines suggesting an immunomodulatory activity. PMID:23320022

Machado, Joleen Lopes; Assunção, Anne Karine Martins; da Silva, Mayara Cristina Pinto; Dos Reis, Aramys Silva; Costa, Graciomar Conceição; Arruda, Diêgo de Sousa; Rocha, Bruno Alves; Vaz, Mirela Mara de Oliveira Lima Leite; Paes, Antonio Marcus de Andrade; Guerra, Rosane Nassar Meireles; Berretta, Andresa Aparecida; do Nascimento, Flávia Raquel Fernandes

2012-01-01

57

Macrophage activation and leishmanicidal activity by galactomannan and its oxovanadium (IV/V) complex in vitro.  

PubMed

Compounds that activate macrophage antimicrobial activity are potential targets for treatment of leishmaniasis. The present study investigated the in vitro immunomodulatory effects of a galactomannan (GALMAN-A) isolated from seeds of Mimosa scabrella and its oxovanadium (IV/V) complex (GALMAN-A:VO(2+)/VO(3+)) on macrophage activity. GALMAN-A increased nitric oxide levels by ~33% at a concentration of 250?g/ml, while GALMAN-A:VO(2+)/VO(3+) decreased nitric oxide levels by ~33% at a concentration of 50?g/ml. Furthermore, GALMAN-A increased interleukin-1 beta (IL-1?) and interleukin-6 (IL-6) levels by 5.5 and 2.3 times, respectively, at a concentration of 25?g/ml; at the same concentration, GALMAN-A:VO(2+)/VO(3+) promoted an increase in IL-1? and IL-6 production by 8 and 5.5 times, respectively. However, neither GALMAN-A nor GALMAN-A:VO(2+)/VO(3+) affected tumor necrosis factor alpha (TNF-?) or interleukin-10 (IL-10) levels. Importantly, both GALMAN-A and GALMAN-A:VO(2+)/VO(3+) exhibited leishmanicidal activity on amastigotes of Leishmania (L.) amazonensis, reaching ~60% activity at concentrations of 100 and 25?g/ml, respectively. These results indicate that GALMAN-A is three times more potent and its oxovanadium complex is twelve times more potent than Glucantime (300?g/ml), which is the drug of choice in leishmaniasis treatment. The IC50 value for GALMAN-A:VO(2+)/VO(3+) was 74.4?g/ml (0.58?g/ml of vanadium). Thus, the significant activation of macrophages and the noted leishmanicidal effect demonstrate the need for further studies to clarify the mechanisms of action of these compounds. PMID:24169303

Adriazola, Izabela Ono; Evangelista do Amaral, Alex; Amorim, Juliana Carolina; Correia, Beatriz Lourenço; Petkowicz, Carmen Lúcia Oliveira; Mercê, Ana Lucia Ramalho; Noleto, Guilhermina Rodrigues

2014-03-01

58

Macrophage activation syndrome following Acinetobacter baumannii sepsis.  

PubMed

Macrophage activation syndrome (MAS) is a systemic disorder with a high mortality, commonly associated with rheumatological conditions, but which can also occur as a complication of several infections. Here we present a case of MAS following Acinetobacter baumannii sepsis. Early institution of therapy with prednisolone, cyclosporine, colistin, and polymyxin resulted in a prompt clinical recovery. There are very few reported cases of Acinetobacter-related MAS that have been successfully treated. PMID:22285540

John, Teny Mathew; Jacob, Ceena N; Ittycheria, Cherian C; George, Amrutha M; Jacob, Amith G; Subramaniyam, Saji; Puthiyaveettil, Jabbar; Jayaprakash, R

2012-03-01

59

Macrophage activation induced by Orbignya phalerata Mart.  

PubMed

Babassu is the popular name of Orbignya phalerata Mart. [Arecaceae (Palmae)], which fruits mesocarp has been used in Brazil as medicine for the treatment of pains, constipation, obesity, leukemia, rheumatism, ulcerations, tumors and inflammations. In this study, we investigated the effect of babassu mesocarp flour aqueous extract (BM) on C3H/HePas mice peritoneal cellular migration and macrophage activation by measuring the nitric oxide (NO), hydrogen peroxide (H(2)O(2)) and tumor necrosis factor (TNF) release, spreading activity and major histocompatibility complex (MHC) class II expression. Our results demonstrate that BM injected once ip in mice at 10 and 20 mg/kg increased the cellular influx to the peritoneal cavity, the MHC class II expression and the spreading ability, and also induced the production of NO, TNF and H(2)O(2). The increase in NO-production and MHC expression was also observed after the addition of BM to resident macrophage cultures (100 microg/ml). Thus, BM-treatment was able to activate peritoneal macrophages in vitro and in vivo inducing the production of inflammatory and cytotoxic metabolites, which could justify the popular use of babassu mesocarp in the treatment of tumor diseases, but not in inflammatory pathologies. PMID:16154304

Nascimento, Flávia R F; Barroqueiro, Elizabeth S B; Azevedo, Ana Paula S; Lopes, Adelson S; Ferreira, Susanne C P; Silva, Lucilene A; Maciel, Márcia C G; Rodriguez, Dunia; Guerra, Rosane N M

2006-01-01

60

Enhancement of ATP generation capacity, antioxidant activity and immunomodulatory activities by Chinese Yang and Yin tonifying herbs  

Microsoft Academic Search

Chinese tonifying herbs such as Herba Cistanche, Ganoderma and Cordyceps, which possess antioxidant and\\/or immunomodulatory activities, can be useful in the prevention and treatment of age-related diseases. Pharmacological studies on Yang and Yin tonifying herbs suggest that Yang tonifying herbs stimulate mitochondrial adenosine triphosphate (ATP) generation, presumably through the intermediacy of reactive oxidant species, leading to the enhancement of cellular\\/mitochondrial

Kam Ming Ko; Hoi Yan Leung

2007-01-01

61

Evaluation of some medicinal plants for Immunomodulatory and anti Filarial activity in rodent model.  

E-print Network

??Investigation of immunomodulatory or therapeutic efficacy in three selected Indian medicinal plants namely, Annona squamosa (AS), Murraya koenigii (MK), Withania somnifera (WS) chemotype and Withania… (more)

Soni, Vishal Kumar

2009-01-01

62

Antitumor and immunomodulatory activity of water-soluble polysaccharide from Inonotus obliquus.  

PubMed

The medicinal mushroom Inonotus obliquus has been used as a folk remedy for a long time in Russia and East-European countries to treat gastrointestinal cancer, cardiovascular disease and diabetes. In our study, a water-soluble polysaccharide (ISP2a) was successfully purified from I. obliquus by DEAE-Sepharose CL-6B and Sepharose CL-6B column chromatography. In vivo ISP2a had not only shown antitumor activity, but also could significantly enhance the immune response of tumor-bearing mice. In addition, ISP2a significantly enhanced the lymphocyte proliferation and increased the production of TNF-?. Results of these studies demonstrated that ISP2a had a potential application as natural antitumor agent with immunomodulatory activity. PMID:22840014

Fan, Liuping; Ding, Shaodong; Ai, Lianzhong; Deng, Kequan

2012-10-01

63

In vitro study of the antioxidant and immunomodulatory activity of aqueous infusion of Bidens pilosa.  

PubMed

Bidens pilosa is an annual plant from tropical America with anti-inflammatory properties in hepatitis, laryngitis, headache and digestive disorders, among others. Its wide pharmacological applications can be attributed to its chemical composition, with inhibitory effects on pathogenic microorganisms and flavonoids, which show strong antioxidant capacities. We investigated the antioxidant activity of an aqueous infusion of Bidens pilosa by studying its protective effect on the hemolysis induced by an initiator of radicals such as 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH). The immunomodulatory activity of the infusion was tested using whole blood cells. Cytokine production increased in whole blood stimulated or not by lipopolysaccharides (LPSs). The infusion is also characterized by its capacity to protect erythrocytes from the phototoxic effect of chlorpromazine, which allows its use as a potential photoprotector. Finally, it did not show ocular irritation, as demonstrated by the effect on hemoglobin denaturation. This study supports the health benefits of the ingestion of the infusion. PMID:15234771

Abajo, Celia; Boffill, María Angeles; del Campo, Jaime; Alexandra Méndez, María; González, Yisel; Mitjans, Montserrat; Pilar Vinardell, María

2004-08-01

64

The FGL2/fibroleukin prothrombinase is involved in alveolar macrophage activation in COPD through the MAPK pathway  

SciTech Connect

Fibrinogen-like protein 2 (FGL2)/fibroleukin has been reported to play a vital role in the pathogenesis of some critical inflammatory diseases by possessing immunomodulatory activity through the mediation of 'immune coagulation' and the regulation of maturation and proliferation of immune cells. We observed upregulated FGL2 expression in alveolar macrophages from peripheral lungs of chronic obstructive pulmonary disease (COPD) patients and found a correlation between FGL2 expression and increased macrophage activation markers (CD11b and CD14). The role of FGL2 in the activation of macrophages was confirmed by the detection of significantly decreased macrophage activation marker (CD11b, CD11c, and CD71) expression as well as the inhibition of cell migration and inflammatory cytokine (IL-8 and MMP-9) production in an LPS-induced FGL2 knockdown human monocytic leukemia cell line (THP-1). Increased FGL2 expression co-localized with upregulated phosphorylated p38 mitogen-activated protein kinase (p38-MAPK) in the lung tissues from COPD patients. Moreover, FGL2 knockdown in THP-1 cells significantly downregulated LPS-induced phosphorylation of p38-MAPK while upregulating phosphorylation of c-Jun N-terminal kinase (JNK). Thus, we demonstrate that FGL2 plays an important role in macrophage activation in the lungs of COPD patients through MAPK pathway modulation.

Liu, Yanling; Xu, Sanpeng; Xiao, Fei; Xiong, Yan; Wang, Xiaojin; Gao, Sui; Yan, Weiming [Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030 (China)] [Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030 (China); Ning, Qin, E-mail: qning@tjh.tjmu.edu.cn [Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030 (China)] [Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030 (China)

2010-05-28

65

Enhanced Immunomodulatory Activity of Gelatin-Encapsulated Rubus coreanus Miquel Nanoparticles  

PubMed Central

The aim of this work was to investigate the immunomodulatory activities of Rubus coreanus Miquel extract-loaded gelatin nanoparticles. The mean size of the produced nanoparticles was 143 ± 18 nm with a bandwidth of 76 nm in the size distribution and a maximum size of ~200 nm, which allows effective nanoparticle uptake by cells. Confocal imaging confirmed this, since the nanoparticles were internalized within 30 min and heterogeneously distributed throughout the cell. Zeta-potential measurements showed that from pH = 5 onwards, the nanoparticles were highly negatively charged, which prevents agglomeration to clusters by electrostatic repulsion. This was confirmed by TEM imaging, which showed a well dispersed colloidal solution. The encapsulation efficiency was nearly 60%, which is higher than for other components encapsulated in gelatin nanoparticles. Measurements of immune modulation in immune cells showed a significant effect by the crude extract, which was only topped by the nanoparticles containing the extract. Proliferation of B-, T- and NK cells was notably enhanced by Rubus coreanus-gelatin nanoparticles and in general ~2–3 times higher than control and on average ~2 times higher than ferulic acid. R. coreanus-gelatin nanoparticles induced cytokine secretion (IL-6 and TNF-?) from B- and T-cells on average at a ~2–3 times higher rate compared with the extract and ferulic acid. In vivo immunomodulatory activity in mice fed with R. coreanus-gelatin nanoparticles at 1 mL/g body weight showed a ~5 times higher antibody production compared to control, a ~1.3 times higher production compared to the extract only, and a ~1.6 times higher production compared to ferulic acid. Overall, our results suggest that gelatin nanoparticles represent an excellent transport vehicle for Rubus coreanus extract and extracts from other plants generally used in traditional Asian medicine. Such nanoparticles ensure a high local concentration that results in enhancement of immune cell activities, including proliferation, cytokine secretion, and antibody production. PMID:22272118

Seo, Yong Chang; Choi, Woon Yong; Lee, Choon Geun; Cha, Seon Woo; Kim, Young Ock; Kim, Jin-Chul; Drummen, Gregor P. C.; Lee, Hyeon Yong

2011-01-01

66

Genetically Engineered Immunomodulatory Streptococcus thermophilus Strains Producing Antioxidant Enzymes Exhibit Enhanced Anti-Inflammatory Activities  

PubMed Central

The aims of this study were to develop strains of lactic acid bacteria (LAB) having both immunomodulatory and antioxidant properties and to evaluate their anti-inflammatory effects both in vitro, in different cellular models, and in vivo, in a mouse model of colitis. Different Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus strains were cocultured with primary cultures of mononuclear cells. Analysis of the pro- and anti-inflammatory cytokines secreted by these cells after coincubation with candidate bacteria revealed that L. delbrueckii subsp. bulgaricus CRL 864 and S. thermophilus CRL 807 display the highest anti-inflammatory profiles in vitro. Moreover, these results were confirmed in vivo by the determination of the cytokine profiles in large intestine samples of mice fed with these strains. S. thermophilus CRL 807 was then transformed with two different plasmids harboring the genes encoding catalase (CAT) or superoxide dismutase (SOD) antioxidant enzymes, and the anti-inflammatory effects of recombinant streptococci were evaluated in a mouse model of colitis induced by trinitrobenzenesulfonic acid (TNBS). Our results showed a decrease in weight loss, lower liver microbial translocation, lower macroscopic and microscopic damage scores, and modulation of the cytokine production in the large intestines of mice treated with either CAT- or SOD-producing streptococci compared to those in mice treated with the wild-type strain or control mice without any treatment. Furthermore, the greatest anti-inflammatory activity was observed in mice receiving a mixture of both CAT- and SOD-producing streptococci. The addition of L. delbrueckii subsp. bulgaricus CRL 864 to this mixture did not improve their beneficial effects. These findings show that genetically engineering a candidate bacterium (e.g., S. thermophilus CRL 807) with intrinsic immunomodulatory properties by introducing a gene expressing an antioxidant enzyme enhances its anti-inflammatory activities. PMID:24242245

del Carmen, Silvina; de Moreno de LeBlanc, Alejandra; Martin, Rebeca; Chain, Florian; Langella, Philippe; Bermudez-Humaran, Luis G.

2014-01-01

67

Myelin alters the inflammatory phenotype of macrophages by activating PPARs  

PubMed Central

Background Foamy macrophages, containing myelin degradation products, are abundantly found in active multiple sclerosis (MS) lesions. Recent studies have described an altered phenotype of macrophages after myelin internalization. However, mechanisms by which myelin affects the phenotype of macrophages and how this phenotype influences lesion progression remain unclear. Results We demonstrate that myelin as well as phosphatidylserine (PS), a phospholipid found in myelin, reduce nitric oxide production by macrophages through activation of peroxisome proliferator-activated receptor ?/? (PPAR?/?). Furthermore, uptake of PS by macrophages, after intravenous injection of PS-containing liposomes (PSLs), suppresses the production of inflammatory mediators and ameliorates experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The protective effect of PSLs in EAE animals is associated with a reduced immune cell infiltration into the central nervous system and decreased splenic cognate antigen specific proliferation. Interestingly, PPAR?/? is activated in foamy macrophages in active MS lesions, indicating that myelin also activates PPAR?/? in macrophages in the human brain. Conclusion Our data show that myelin modulates the phenotype of macrophages by PPAR activation, which may subsequently dampen MS lesion progression. Moreover, our results suggest that myelin-derived PS mediates PPAR?/? activation in macrophages after myelin uptake. The immunoregulatory impact of naturally-occurring myelin lipids may hold promise for future MS therapeutics. PMID:24252308

2013-01-01

68

Sulfated modification of longan polysaccharide and its immunomodulatory and antitumor activity in vitro.  

PubMed

A water-soluble polysaccharide fraction (LP1) was prepared from Dimocarpus longan Lour. by hot water extraction, DEAE-cellulose and Sephadex G-100 chromatography. Its sulfated derivative (LP1-S) was prepared by the sulfuric acid method. Preliminary tests in vitro showed LP1 and LP1-S could stimulate murine lymphocytes proliferation, increase pinocytic activity of murine macrophages and production of nitric oxide (NO), interleukin 6 (IL-6), IL-1? and tumor necrosis factor-alpha (TNF-?) in macrophages. Furthermore, LP1-S exhibited higher antiproliferative activity against human nasopharyngeal carcinoma HONE1 cells in vitro than LP1, which might be caused by the sulfate group in its structures. These results indicated that the LP1-S might be useful for developing safe antitumor drugs or health food. PMID:24680807

Jiang, Jie; Meng, Fa-Yan; He, Zhou; Ning, Yuan-Ling; Li, Xue-Hua; Song, Hui; Wang, Jing; Zhou, Rui

2014-06-01

69

A novel biofuel cell harvesting energy from activated human macrophages  

Microsoft Academic Search

Macrophage phagocytosis activates NADPH oxidase, an electron transport system in the plasma membrane. This study examined the feasibility of utilizing electrons transferred through the plasma membrane via NADPH oxidase to run a biofuel cell. THP-1 human monocytic cells were chemically stimulated to differentiate into macrophages. Further they were activated to induce a phagocytic response. During differentiation, cells became adherent to

Miho Sakai; Andreas Vonderheit; Xun Wei; Claudia Küttel; Andreas Stemmer

2009-01-01

70

Alternatively Activated Macrophages in Types 1 and 2 Diabetes  

PubMed Central

Macrophages are innate immune cells derived from monocytes, which, in turn, arise from myeloid precursor cells in the bone marrow. Macrophages have many important roles in the innate and adaptive immune response, as well as in tissue homeostasis. Two major populations have been defined: The classically activated macrophages that respond to intracellular pathogens by secreting proinflammatory cytokines and reactive oxygen species and alternatively activated macrophages which are induced during Th2 responses displaying anti-inflammatory activities. Both macrophage populations are central players in diabetes, the first one triggering inflammatory responses which initiates insulitis and pancreatic ? cell death during type 1 diabetes, whereas the second population decreases hyperglycemia, insulitis, and inflammation in the pancreas, thereby negatively regulate type 1 diabetes. Obesity is an important factor in the development of type 2 diabetes; classically activated macrophages are a dominant cell population involved in the establishment of the inflammatory profile, insulin resistance, and activation of inflammatory signals during the development and progression of this disease. In contrast, alternatively activated macrophages regulate the release of proinflammatory cytokines, attenuating adipose tissue inflammation. Here, we review the advantages and disadvantages of these two macrophage populations with regard to their roles in types 1 and 2 diabetes. PMID:23326021

Espinoza-Jimenez, Arlett; Peon, Alberto N.; Terrazas, Luis I.

2012-01-01

71

Immunomodulatory activity of a Unani gold preparation used in Indian system of medicine.  

PubMed

Kushta Tila Kalan (KTK), a gold preparation used in Unani-Tibb is claimed to possess general tonic, anti-infective and rejuvenating properties. We evaluated immunomodulatory activity of KTK in male mice. KTK was orally administered to animals at dosage of 6.25, 12.5, 25 and 50 mg/kg b.w. for 10 days. Beside general immunopathological parameters, cell-mediated immunity was evaluated by measuring delayed type of hypersensitivity response (DTH) while humoral immunity was assessed using plaque forming cell (PFC) assay. KTK augmented both the immune responses at dose levels of 6.25, 12.5 and 25 mg/kg. The optimum activities were recorded at 25 mg/kg. High dose of 50 mg/kg showed suppressive effects on immune functions. The modulatory effects may be attributed to the interactions of gold with herbomineral adjuncts incorporated during the specialized ashing techniques used in the preparation. The results are interesting in view of reported suppressive effects of other gold preparations. PMID:10084336

Bajaj, S; Ahmad, I; Fatima, M; Raisuddin, S; Vohora, S B

1999-02-01

72

Characterization of Two Homogalacturonan Pectins with Immunomodulatory Activity from Green Tea  

PubMed Central

Two natural homogalacturonan (HG) pectins (MW ca. 20 kDa) were isolated from green tea based on their immunomodulatory activity. The crude tea polysaccharides (TPS1 and TPS2) were obtained from green tea leaves by hot water extraction and followed by 40% and 70% ethanol precipitation, respectively. Two homogenous water soluble polysaccharides (TPS1-2a and TPS1-2b) were obtained from TPS1 after purification with gel permeation, which gave a higher phagocytic effect than TPS2. A combination of composition, methylation and configuration analyses, as well as NMR (nuclear magnetic resonance) spectroscopy revealed that TPS1-2a and TPS1-2b were homogalacturonan (HG) pectins consisting of a backbone of 1,4-linked ?-d-galacturonic acid (GalA) residues with 28.4% and 26.1% of carboxyl groups as methyl ester, respectively. The immunological assay results demonstrated that TPS1-2, which consisted mainly of HG pectins, showed phagocytosis-enhancing activity in HL-60 cells. PMID:24901527

Wang, Huijun; Wei, Guodong; Liu, Fei; Banerjee, Gautam; Joshi, Manoj; Bligh, S. W. Annie; Shi, Songshan; Lian, Hui; Fan, Hongwei; Gu, Xuelan; Wang, Shunchun

2014-01-01

73

Evaluation of the immunomodulatory activities of royal jelly components in vitro.  

PubMed

In this work the effect of different components isolated from royal jelly (RJ) was studied using an in vitro rat T-cell proliferation assay. We found that lower concentrations of MEL 174 (final water extract of RJ) and MEL 147 (3-10-dihydroxydecanoic acid) stimulated T-cell proliferation, triggered by concanavalin A (Con-A) and the process was followed by an increase in the production of interleukin-2 (IL-2). Higher concentrations of MEL 174, MEL 247 (dry powder of RJ) and MEL 138 (trans-10-hydroxydec-2-enoic acid) inhibited T-cell proliferation. The inhibition of T-cell proliferation in the presence of MEL 174 was followed by a decrease in IL-2 production, which was partly abrogated by exogenous IL-2, a decrease in nitric oxide (NO) production and increased apoptosis. In conclusion, our results showed the complexity of biological activity of RJ and suggest that its water extract possesses the most potent immunomodulatory activity in vitro. PMID:18075862

Gasic, Sonja; Vucevic, Dragana; Vasilijic, Sasa; Antunovic, Mirjana; Chinou, Ioanna; Colic, Miodrag

2007-01-01

74

Human macrophage polarization in vitro: maturation and activation methods compared.  

PubMed

Macrophages form a heterogeneous cell population displaying multiple functions, and can be polarized into pro- (M1) or anti-inflammatory (M2) macrophages, by environmental factors. Their activation status reflects a beneficial or detrimental role in various diseases. Currently several in vitro maturation and activation protocols are used to induce an M1 or M2 phenotype. Here, the impact of different maturation factors (NHS, M-CSF, or GM-CSF) and activation methods (IFN-?/LPS, IL-4, dexamethason, IL-10) on the macrophage phenotype was determined. Regarding macrophage morphology, pro-inflammatory (M1) activation stimulated cell elongation, and anti-inflammatory (M2) activation induced a circular appearance. Activation with pro-inflammatory mediators led to increased CD40 and CD64 expression, whereas activation with anti-inflammatory factors resulted in increased levels of MR and CD163. Production of pro-inflammatory cytokines was induced by activation with IFN-?/LPS, and TGF-? production was enhanced by the maturation factors M-CSF and GM-CSF. Our data demonstrate that macrophage marker expression and cytokine production in vitro is highly dependent on both maturation and activation methods. In vivo macrophage activation is far more complex, since a plethora of stimuli are present. Hence, defining the macrophage activation status ex vivo on a limited number of markers could be indecisive. From this study we conclude that maturation with M-CSF or GM-CSF induces a moderate anti- or pro-inflammatory state respectively, compared to maturation with NHS. CD40 and CD64 are the most distinctive makers for human M1 and CD163 and MR for M2 macrophage activation and therefore can be helpful in determining the activation status of human macrophages ex vivo. PMID:24916404

Vogel, Daphne Y S; Glim, Judith E; Stavenuiter, Andrea W D; Breur, Marjolein; Heijnen, Priscilla; Amor, Sandra; Dijkstra, Christine D; Beelen, Robert H J

2014-09-01

75

QSAR, docking and in vivo studies for immunomodulatory activity of isolated triterpenoids from Eucalyptus tereticornis and Gentiana kurroo.  

PubMed

Two triterpenoids ursolic acid (1) and lupeol (2) isolated and characterized from Eucalyptus tereticornis and Gentiana kurroo were subjected to in silico QSAR modeling and docking studies and later the predicted results were confirmed through in vivo experiments. QSAR modeling results showed that both the triterpenoids possess immunomodulatory and anti-inflammatory activity comparable to boswellic and cichoric acids, but were less active than levamisol. Docking results suggested that both the triterpenoids (1 and 2) showed immune modulatory and anti-inflammatory activity due to high binding affinity to human receptors viz., NF-kappaB p52 (-50.549 kcal/mol), tumor necrosis factor (TNF-alpha) (-47.632 kcal/mol), nuclear factor NF-Kappa-B P50 (-16.798 kcal/mol) and cyclooxygenase-2 (-55.244 kcal/mol). Further both the triterpenoids (1 and 2) were subjected to in vivo immunomodulatory activity in female Swiss albino mice. The experimental mice were divided into nine groups, each comprised of six mice. These received oral treatment for a period of 28 days. The triterpenoids (1 and 2) showed significant increased in humoral immune function, but no significant changes were observed in cell mediated immune response and hematological parameters. The in silico and in vivo experimental data suggested that both the triterpenoids 1 and 2 may be considered as potential immunomodulatory drug-like molecules. PMID:22659375

Maurya, Anupam; Khan, Feroz; Bawankule, Dnyaneshwar Umrao; Yadav, Dharmendra Kumar; Srivastava, Santosh Kumar

2012-08-30

76

Molecular properties of water-unextractable proteoglycans from Hypsizygus marmoreus and their in vitro immunomodulatory activities.  

PubMed

Four proteoglycans were sequentially extracted from Hypsizygus marmoreus using 0.1 M NaOH (alkali-soluble proteoglycans [F1] and alkali-insoluble proteoglycans [F3]) and 0.1 M HCl (acid-soluble proteoglycans [F2] and acid-insoluble proteoglycans [F4]), and their structures and immunomodulatory activities were investigated. The proteoglycans were found to contain carbohydrates (19.8-82.4%) with various amounts of proteins (7.7-67.3%), and glucose was the major monosaccharide unit present, along with trace amounts of galactose. The molecular weights (Mw) and the radius of gyration (Rg) of these proteoglycans showed ranges of 16 × 10(4)-19,545 × 10(4) g/mol and 35-148 nm, respectively, showing significant variations in their molecular conformations. The backbones of F1 and F2 were mainly connected through a-(1?3), (1?4) and b-(1?6)-glycosidic linkages with some branches. The F1 and F2 proteoglycans significantly stimulated Raw264.7 cells to release nitric oxide (NO), prostaglandin E2 (PGE(2)) and various cytokines, such as IL-1?, TNF-? and IL-6 by inducing their mRNA expressions. PMID:22202808

Bao, Hong Hui; Tarbasa, Mehdi; Chae, Hee Mun; You, Sang Guan

2011-01-01

77

Evaluation of immunomodulatory activity of an extract of andrographolides from Andographis paniculata.  

PubMed

The immunomodulatory activity of HN-02, an extract containing a mixture of andrographolides (i.e., andrographolide [88 +/- 5 %] plus 14-deoxyandrographolide and 14-deoxy-11,12-didehydroandrographolide together [12 +/- 3 %]) in a pure powder form was evaluated at 1.0, 1.5, and 2.5 mg/kg on different in vivo and in vitro experimental models. In a delayed-type hypersensitivity (DTH) mouse model, potentiation of the DTH reaction was observed after treatment with cyclophosphamide (CYP) and HN-02 individually. However, CYP potentiation of the DTH reaction was reversed by HN-02 pretreatment. Furthermore, HN-02 treatment elevated the depressed hemagglutination antibody (HA) titer and increased the number of plaque-forming cells (PFCs) in the spleen cells of mice that had been treated with CYP and challenged with sheep red blood cells (SRBC). Further, it was also found that HN-02 treatment stimulated phagocytosis in mice. A significant increase in total WBC count and relative weight of spleen and thymus was observed in mice during 30 days of treatment with HN-02. The present experimental findings demonstrate that HN-02 has the ability to enhance immune function, possibly through modulation of immune responses altered during antigen interaction, and to reverse the immunosuppression induced by CYP. PMID:19263340

Naik, Suresh R; Hule, Amolkumar

2009-06-01

78

Toll-like receptor 4-mediated ROS signaling pathway involved in Ganoderma atrum polysaccharide-induced tumor necrosis factor-? secretion during macrophage activation.  

PubMed

Ganoderma atrum has been used as Chinese traditional medicine and healthful mushroom for thousands of years. The polysaccharide is regarded as the major bioactive substances in G. atrum. To delineate the underlying mechanism and signaling cascade involved in the immunomodulatory property of G. atrum polysaccharide (PSG-1). Specifically, this study is designed to examine the possibility of TLR4 as a candidate receptor interacted with G. atrum polysaccharide (PSG-1) and elucidate the role of reactive oxygen species (ROS) in PSG-1-induced tumor necrosis factor-? (TNF-?) production during macrophage activation. Flow cytometric and confocal laser-scanning microscopy analysis showed that fluorescence-labeled PSG-1 bind specifically to the macrophages. Moreover, PSG-1 stimulated TNF-? secretion of peritoneal macrophages from C3H/HeN mice, but not from C3H/HeJ mice. PSG-1-indcued TNF-? production was suppressed by anti-TLR4 mAb. Furthermore, ROS production was mediated by TLR4, and NADPH oxidase-derived ROS act as upstream of phosphoinositide 3-kinase(PI3K)/Akt/mitogen-activated protein kinases(MAPKs)/nuclear factor(NF)-?B signaling pathway in the regulation of PSG-1 stimulated TNF-? production. Taken together, we conclude that PSG-1 induces TNF-? secretion through TLR4/ROS/PI3K/Akt/MAPKs/NF-?B pathways during macrophage activation. Our findings provide a molecular basis for the potential of PSG-1 as a novel immunomodulatory agent. PMID:24447977

Yu, Qiang; Nie, Shao-Ping; Wang, Jun-Qiao; Yin, Peng-Fei; Huang, Dan-Fei; Li, Wen-Juan; Xie, Ming-Yong

2014-04-01

79

Synthetic Mimics of Antimicrobial Peptides with Immunomodulatory Responses  

PubMed Central

A new series of aryl-based SMAMPs with antimicrobial activity and selectivity have been developed via systematic tuning of aromatic groups and charge. The addition of a pendant aromatic group improved the antimicrobial activity against gram-negative bacteria, while the addition of charge improved the selectivity. SMAMP 4, with six charges and a naphthalene central ring, demonstrated a selectivity of 200 against both S. aureus and E. coli, compared to a selectivity of 8 for the peptide MSI-78. In addition to the direct antimicrobial activity, SMAMP 4 exhibited specific immunomodulatory activities in macrophages both in the presence and absence of LPS, a TLR agonist. SMAMP 4 also induced the production of the neutrophil chemo-attractant, murine KC, in mouse primary cells. This is the first, non-peptidic SMAMP demonstrating both good antimicrobial and immunomodulatory activity. PMID:22697149

Thaker, Hitesh D.; Som, Abhigyan; Ayaz, Furkan; Scott, Richard W.; Anguita, Juan; Tew, Gregory N.

2012-01-01

80

Anti-tumor and immunomodulatory activity of intraperitoneal IFN-gamma in ovarian carcinoma patients with minimal residual tumor after chemotherapy.  

PubMed

Eight patients with epithelial ovarian carcinoma persisting after chemotherapy, selected for having a residual tumor no larger than 1 cm in diameter, were treated intra-peritoneally (i.p.) with recombinant interferon-gamma twice weekly for 3 months. Toxicity consisted of fever and malaise in all patients and a transient rise in hepatic enzyme levels in 3 patients. The cytotoxic function of peripheral blood and peritoneal tumor-associated lymphocytes (TAL) and macrophages (TAM), was studied using cell lines as targets. I.p. IFN-gamma augmented the cytotoxic activity of lymphocytes and mononuclear phagocytes: stimulation was more marked and more frequently observed with TAL and occasionally TAM than with blood effectors, suggesting preferential modulation at the site of tumor growth and IFN administration. Surgical laparotomy revealed that 1 patient had a complete response, 2 a partial response and 2 had stable disease, while 3 patients had progressive disease. In this small series of patients there was no obvious, strict correlation between immunomodulation by IFN-gamma and clinical response. These results indicate that, in contrast to its lack of activity in advanced ovarian carcinoma, IFN-gamma has definite immunomodulatory and antitumor activity in the presence of limited tumor burden. PMID:1563843

Colombo, N; Peccatori, F; Paganin, C; Bini, S; Brandely, M; Mangioni, C; Mantovani, A; Allavena, P

1992-04-22

81

Maternal immune activation leads to activated inflammatory macrophages in offspring.  

PubMed

Several epidemiological studies have shown an association between infection or inflammation during pregnancy and increased risk of autism in the child. In addition, animal models have illustrated that maternal inflammation during gestation can cause autism-relevant behaviors in the offspring; so called maternal immune activation (MIA) models. More recently, permanent changes in T cell cytokine responses were reported in children with autism and in offspring of MIA mice; however, the cytokine responses of other immune cell populations have not been thoroughly investigated in these MIA models. Similar to changes in T cell function, we hypothesized that following MIA, offspring will have long-term changes in macrophage function. To test this theory, we utilized the poly (I:C) MIA mouse model in C57BL/6J mice and examined macrophage cytokine production in adult offspring. Pregnant dams were given either a single injection of 20mg/kg polyinosinic-polycytidylic acid, poly (I:C), or saline delivered intraperitoneally on gestational day 12.5. When offspring of poly (I:C) treated dams reached 10weeks of age, femurs were collected and bone marrow-derived macrophages were generated. Cytokine production was measured in bone marrow-derived macrophages incubated for 24h in either growth media alone, LPS, IL-4/LPS, or IFN-?/LPS. Following stimulation with LPS alone, or the combination of IFN-?/LPS, macrophages from offspring of poly (I:C) treated dams produced higher levels of IL-12(p40) (p<0.04) suggesting an increased M1 polarization. In addition, even without the presence of a polarizing cytokine or LPS stimulus, macrophages from offspring of poly (I:C) treated dams exhibited a higher production of CCL3 (p=0.05). Moreover, CCL3 levels were further increased when stimulated with LPS, or polarized with either IL-4/LPS or IFN-?/LPS (p<0.05) suggesting a general increase in production of this chemokine. Collectively, these data suggest that MIA can produce lasting changes in macrophage function that are sustained into adulthood. PMID:24566386

Onore, Charity E; Schwartzer, Jared J; Careaga, Milo; Berman, Robert F; Ashwood, Paul

2014-05-01

82

LFA-1-dependent tumoricidal activity of cisplatin-treated macrophages.  

PubMed

The role of leucocyte function associated antigen-1 (LFA-1) (CD11a/18) in the tumoricidal activity of cisplatin-treated macrophages was investigated. Anti-LFA-1 antibodies inhibited cisplatin-induced macrophage cytotoxicity towards three different tumour cell lines. The decrease in tumoricidal activity of cisplatin-treated macrophages was attributed to their decreased binding to tumour cells in the presence of anti-LFA-1 (CD11a/18) antibodies. Western blot analysis revealed that cisplatin treatment leads to the expression of LFA-1 on macrophages which otherwise remains non-detectable. Because there is no information regarding the mechanism of cisplatin-induced LFA-1 expression and tumour cell binding by macrophages, the role of various second messenger molecules in these processes was investigated. Results suggest that protein phosphatase 2A (PP2A) is not involved in these processes whereas protein tyrosine phosphatases (PTP) negatively regulate LFA-1 expression and tumour-cell binding of cisplatin-treated macrophages. Inhibitors of protein phosphatase 1 (PP1), protein kinase C (PKC), protein tyrosine kinase (PTK), calmodulin and calmodulin-dependent kinase-II (CamK II) prevented LFA-1 expression on cisplatin-treated macrophages. A comparison with earlier results indicated that LFA-expression follows a distinct signalling pathway which is separate from the signalling pathway involved in NO or tumour necrosis factor/interleukin-1 (TNF/IL-1) expression in cisplatin-stimulated macrophages. PMID:9723775

Singh, R A; Sodhi, A

1998-08-01

83

Antiorthostatic suspension stimulates profiles of macrophage activation in mice  

NASA Technical Reports Server (NTRS)

The antiorthostatic suspension model simulates certain physiological effects of spaceflight. We have previously reported BDF1 mice suspended by the tail in the antiorthostatic orientation for 4 days express high levels of resistance to virulent Listeria monocytogenesinfection. In the present study, we examined whether the increased resistance to this organism correlates with profiles of macrophage activation, given the role of the macrophage in killing this pathogen in vivo. We infected BDF1 mice with a lethal dose of virulent L. monocytogenes on day 4 of antiorthostatic suspension and 24 h later constructed profiles of macrophage activation. Viable listeria could not be detected in mice suspended in the antiorthostatic orientation 24 h after infection. Flow cytometric analysis revealed the numbers of granulocytes and mononuclear phagocytes in the spleen of infected mice were not significantly altered as a result of antiorthostatic suspension. Splenocytes from antiorthostatically suspended infected mice produced increased titers of IL-1. Serum levels of neopterin, a nucleotide metabolite secreted by activated macrophages, were enhanced in mice infected during antiorthostatic suspension, but not in antiorthostatically suspended naive mice. Splenic macrophages from mice infected on day 4 of suspension produced enhanced levels of lysozyme. In contrast to the results from antiorthostatically suspended infected mice, macrophages from antiorthostatically suspended uninfected mice did not express enhanced bactericidal activities. The collective results indicate that antiorthostatic suspension can stimulate profiles of macrophage activation which correlate with increased resistance to infection by certain classes of pathogenic bacteria.

Miller, E. S.; Bates, R. A.; Koebel, D. A.; Sonnenfeld, G.

1999-01-01

84

Pulmonary macrophages are attracted to inhaled particles through complement activation.  

PubMed

Pulmonary macrophages play a central role in clearing inhaled particles from the lung. Previously, we showed that inhaled asbestos fibers activate complement-dependent chemotactic factors on alveolar surfaces to facilitate macrophage recruitment to sites of fiber deposition. In the studies presented here, we have tested a variety of inorganic particles for complement activation in vitro and correlated these data with results on particle-induced macrophage accumulation in vivo. We found that significant chemotactic activity was activated in rat serum and concentrated lavaged proteins by chrysotile and crocidolite asbestos, iron-coated chrysotile asbestos, fiberglass, and wollastonite fibers, as well as by carbonyl iron and zymosan particles. Ash from the Mt. St. Helens volcano did not induce chemotactic activity in either the serum or lavaged proteins. Rats were exposed to brief aerosols of each of the particles listed above (except zymosan). All the particle types studied were deposited primarily at first alveolar duct bifurcations. In addition, all of the particles, except Mt. St. Helens ash, induced at 48 h postexposure significant accumulations of macrophages at these sites. Time-course studies of carbonyl iron particle exposure demonstrated that iron induced a rapid macrophage response, but both particles and phagocytic macrophages were cleared from alveolar surfaces within 8 days after exposure. The Mt. St. Helens ash induced no macrophage accumulation at any time postexposure. We conclude that particles with a wide variety of physical characteristics are capable of activating complement and consequently attracting macrophages, both in vitro and in vivo. We suggest that complement activation is a mechanism through which pulmonary macrophages can detect inhaled particles on alveolar surfaces. PMID:2830106

Warheit, D B; Overby, L H; George, G; Brody, A R

1988-01-01

85

EFFECT OF NORMAL AND ACTIVATED HUMAN MACROPHAGES ON TOXOPLASMA GONDII  

PubMed Central

Human macrophages derived from in vitro culture of peripheral blood monocytes were studied under a variety of conditions to determine their microbicidal capacity for the obligate intracellular protozoan, Toxoplasma gondii. The effect of macrophages on intracellular Toxoplasma was evaluated morphologically by light and phase microscopy and by autoradiography. When macrophages from dye test (DT)-negative or DT-positive individuals were infected with Toxoplasma in the presence of normal human serum, the organisms were able to multiply intracellularly with resultant destruction of the monolayer. Once organisms were intracellular, the presence of antibody-containing serum in the medium did not alter this inability of the macrophages to kill Toxoplasma. However, when Toxoplasma were incubated in the presence of heat-inactivated DT-positive serum just before infection of the monolayers, the intracellular organisms were inhibited or killed by normal macrophages. Attempts were made to activate macrophages in vitro to kill Toxoplasma. Macrophages incubated in the presence of sensitized lymphocytes and Streptokinase-Streptodornase (SK-SD) or Toxoplasma lysate antigen (TLA) were found to kill Toxoplasma when compared to macrophages incubated in the presence of lymphocytes from DT-negative individuals and TLA or lymphocytes alone. Thus, in vitro induction of resistance (both specifically and nonspecifically) in human macrophages was accomplished by culturing these cells in the presence of specifically sensitized lymphocytes and antigen. These results suggest that, as in the mouse model, activated human macrophages have the ability to inhibit or kill intracellular Toxoplasma and that these cells may be important as effector cells in cell-mediated immunity (CMI) to toxoplasmosis in man. PMID:4132992

Anderson, Seth E.; Remington, Jack S.

1974-01-01

86

Nanotube sensors Probing Macrophage Activity with Carbon-Nanotube  

E-print Network

cellular activity. As part of the immune system, macrophages can ingest and digest pathogens in a process devices is placed in a home- built flow-cell on top of a Peltier element to maintain the temperature

Dekker, Cees

87

HDAC6 Deacetylase Activity Is Critical for Lipopolysaccharide-Induced Activation of Macrophages  

PubMed Central

Activated macrophages play an important role in both innate and adaptive immune responses, and aberrant activation of macrophages often leads to inflammatory and immune disorders. However, the molecular mechanisms of how macrophages are activated are not fully understood. In this study, we identify a novel role for histone deacetylse 6 (HDAC6) in lipopolysaccharide (LPS)-induced macrophage activation. Our data show that suppression of HDAC6 activity significantly restrains LPS-induced activation of macrophages and production of pro-inflammatory cytokines. Further study reveals that the regulation of macrophage activation by HDAC6 is independent of F-actin polymerization and filopodium formation; instead, it is mediated by the effects of HDAC6 on cell adhesion and microtubule acetylation. These data thus suggest that HDAC6 is an important regulator of LPS-induced macrophage activation and might be a potential target for the management of inflammatory disorders. PMID:25330030

Liu, Zhu; Ran, Jie; Li, Yuanyuan; Wang, Jian; Yang, Yang; Zhou, Jun; Li, Dengwen; Liu, Min

2014-01-01

88

Activity of the Novel Immunomodulatory Compound Tucaresol against Experimental Visceral Leishmaniasis  

PubMed Central

Tucaresol, a novel immunomodulator, was inactive against Leishmania donovani amastigotes in both peritoneal and bone marrow macrophages in vitro at concentrations between 100 and 1 ?M, with toxicity to macrophages and parasites at 300 ?M. However, against L. donovani in BALB/c mice at doses between 80 and 1.25 mg/kg of body weight administered once daily by the oral route during days 7 to 11 of infection, an optimal dose of 5 mg/kg produced a 43.8 to 62.4% suppression of liver amastigotes, with significantly reduced activity at the extremes of the dose range. This response was not related to levels of infection. No interaction with the standard pentavalent antimonial sodium stibogluconate (Pentostam) was observed during this period of infection. The optimum dose of 5 mg/kg was ineffective when administered during the first week of infection and was most effective against the liver infection when administered during weeks 2 to 3 of infection (42.3 to 46.8% inhibition) and against the splenic infection when administered during week 6 of infection (59.5% inhibition). The optimum dose of tucaresol against L. donovani in C57BL/6 mice was 5 mg/kg, which produced a 40.8 to 48.7% suppression of liver amastigotes when administered in a range of 80 to 1.25 mg/kg during days 7 to 11 of infection. The drug had no activity against L. donovani infections in C.B-17 scid mice when the same regimen was used. PMID:10817698

Smith, Aden C.; Yardley, Vanessa; Rhodes, John; Croft, Simon L.

2000-01-01

89

C/EBP? regulates macrophage activation and systemic metabolism.  

PubMed

Macrophage infiltration plays an important role in obesity-induced insulin resistance. CCAAT enhancer-binding protein-? (C/EBP?) is a transcription factor that is highly expressed in macrophages. To examine the roles of C/EBP? in regulating macrophage functions and energy homeostasis, macrophage-specific C/EBP? knockout (M?KO) mice were created. Chow-fed M?KO mice exhibited higher body fat mass and decreased energy expenditure despite no change in food intake. However, the obese phenotype disappeared after high-fat (HF) diet feeding. Although there was a transient decrease in insulin sensitivity of chow-fed young M?KO mice, systemic insulin sensitivity was protected during HF-feeding due to preserved insulin sensitivity in skeletal muscle. We also found that C/EBP?-deficient macrophages exhibited a blunted response of cytokine-induced expression of M1 and M2 macrophage markers, suggesting that C/EBP? controls both M1 and M2 polarization. Consistent with decreased exercise capacity, mitochondrial respiration rates and signal pathways for fatty acid oxidation were remarkably reduced in the skeletal muscle of chow-fed M?KO mice. Furthermore, expression levels of inflammatory cytokines were reduced in skeletal muscle of HF-fed M?KO mice. Together, these results imply that C/EBP? is required for macrophage activation, which plays an important role in maintaining skeletal muscle energy metabolism. PMID:24691027

Lee, Bonggi; Qiao, Liping; Lu, Min; Yoo, Hyung Sun; Cheung, Wai; Mak, Robert; Schaack, Jerome; Feng, Gen-Sheng; Chi, Nai-Wen; Olefsky, Jerrold M; Shao, Jianhua

2014-05-15

90

Carbohydrate composition and immunomodulatory activity of different glycoforms of ?1-acid glycoprotein  

Microsoft Academic Search

The acute phase protein, ?1-acid glycoprotein (AGP), is a normal constituent of human blood (0.2–1 mg ml?1) and its glycosylation\\u000a and concentration in the blood change during inflammation. In this review of our recent work, we discuss the immunomodulatory\\u000a properties of AGP in connection with the structure of its carbohydrate chains.\\u000a \\u000a AGP samples prepared from normal donor serum (nAGP), serum

Svetlana D. Shiyan; Nicolai V. Bovin

1997-01-01

91

Immunomodulatory activities of polysaccharides isolated from Taxillus chinensis and Uncaria rhyncophylla.  

PubMed

Taxillus chinensis and Uncaria rhyncophylla are the herbs used in traditional Chinese anticancer formulations. During the past decade, research on plant polysaccharides has gained importance due to their therapeutic value and minimum side effects. In this study, hot water extraction method was employed to isolate polysaccharides from the stems of T. chinensis and stems with hooks of U. rhyncophylla. Size-exclusion chromatography was then used for further fractionation. Separated fractions from T. chinensis were designated as TCP-1, TCP-2 and TCP-3 and those from U. rhyncophylla were termed UC-1 and UC-2. Their sugar compositions were estimated using gas chromatography that revealed the presence fructose, glucose, xylose, arbinose, and rhamnose. Amino acid analysis of these fractions has indicated that they are protein-bound polysaccharides. The antioxidant activities were investigated using DPPH and yeast assays. The ability of these polysaccharide fractions to stimulate mouse macrophages was measured using Griess reagent and ELISA test. The results revealed that some of the isolated fractions (TCP-2, TCP-3, UC-1 and UC-2) displayed significant antioxidant activities and were also found to be effective immunomodulators in a concentration-dependent manner. Outcomes of this research strongly indicate that U. rhyncophylla and T. chinensis have therapeutic potential to be used for the treatment of cancer. PMID:24053827

Zhang, Lin; Koyyalamudi, Sundar Rao; Jeong, Sang Chul; Reddy, Narsimha; Bailey, Trevor; Longvah, T

2013-11-01

92

Umbilical cord-derived mesenchymal stem cells retain immunomodulatory and anti-oxidative activities after neural induction?  

PubMed Central

The immunomodulatory and anti-oxidative activities of differentiated mesenchymal stem cells contribute to their therapeutic efficacy in cell-replacement therapy. Mesenchymal stem cells were isolated from human umbilical cord and induced to differentiate with basic fibroblast growth factor, nerve growth factor, epidermal growth factor, brain-derived neurotrophic factor and forskolin. The mesenchymal stem cells became rounded with long processes and expressed the neural markers, Tuj1, neurofilament 200, microtubule-associated protein-2 and neuron-specific enolase. Nestin expression was significantly reduced after neural induction. The expression of immunoregulatory and anti-oxidative genes was largely unchanged prior to and after neural induction in mesenchymal stem cells. There was no significant difference in the effects of control and induced mesenchymal stem cells on lymphocyte proliferation in co-culture experiments. However, the expression of human leukocyte antigen-G decreased significantly in induced neuron-like cells. These results suggest that growth factor-based methods enable the differentiation of mesenchymal stem cell toward immature neuronal-like cells, which retain their immunomodulatory and anti-oxidative activities. PMID:25337112

Li, Jianjun; Li, Dong; Ju, Xiuli; Shi, Qing; Wang, Dakun; Wei, Fengcai

2012-01-01

93

Free radical scavenging and immunomodulatory activities of Ganoderma lucidum polysaccharides derivatives.  

PubMed

Polysaccharides extracted from the fruit body of Ganoderma lucidum were sulfated and carboxymethylated as reported. Free radical scavenging and immunomodulatory effects of sulfated and carboxymethylated polysaccharides were studied. Generally, sulfated polysaccharides showed better bioactivities than that of carboxymethylated polysaccharides. The two derivatives were injected intraperitoneally with or without 5-fluorouracil over a period of 7 days in BALB/c female mice. The polysaccharide derivatives increased mouse thymus and spleen index, an indication of improved immunity in mice. At the same time, they improved superoxide dismutase and glutathione peroxidase contents in the mice body. PMID:23044102

Wang, Jianguo; Wang, Yutang; Liu, Xuebo; Yuan, Yahong; Yue, Tianli

2013-01-01

94

Periodontitis-activated monocytes/macrophages cause aortic inflammation  

PubMed Central

A relationship between periodontal disease and atherosclerosis has been suggested by epidemiological studies. Ligature-induced experimental periodontitis is an adequate model for clinical periodontitis, which starts from plaque accumulation, followed by inflammation in the periodontal tissue. Here we have demonstrated using a ligature-induced periodontitis model that periodontitis activates monocytes/macrophages, which subsequently circulate in the blood and adhere to vascular endothelial cells without altering the serum TNF-? concentration. Adherent monocytes/macrophages induced NF-?B activation and VCAM-1 expression in the endothelium and increased the expression of the TNF-? signaling cascade in the aorta. Peripheral blood-derived mononuclear cells from rats with experimental periodontitis showed enhanced adhesion and increased NF-?B/VCAM-1 in cultured vascular endothelial cells. Our results suggest that periodontitis triggers the initial pathogenesis of atherosclerosis, inflammation of the vasculature, through activating monocytes/macrophages. PMID:24893991

Miyajima, Shin-ichi; Naruse, Keiko; Kobayashi, Yasuko; Nakamura, Nobuhisa; Nishikawa, Toru; Adachi, Kei; Suzuki, Yuki; Kikuchi, Takeshi; Mitani, Akio; Mizutani, Makoto; Ohno, Norikazu; Noguchi, Toshihide; Matsubara, Tatsuaki

2014-01-01

95

ROS play a critical role in the differentiation of alternatively activated macrophages and the occurrence of tumor-associated macrophages  

PubMed Central

Differentiation to different types of macrophages determines their distinct functions. Tumor-associated macrophages (TAMs) promote tumorigenesis owing to their proangiogenic and immune-suppressive functions similar to those of alternatively activated (M2) macrophages. We report that reactive oxygen species (ROS) production is critical for macrophage differentiation and that inhibition of superoxide (O2?) production specifically blocks the differentiation of M2 macrophages. We found that when monocytes are triggered to differentiate, O2? is generated and is needed for the biphasic ERK activation, which is critical for macrophage differentiation. We demonstrated that ROS elimination by butylated hydroxyanisole (BHA) and other ROS inhibitors blocks macrophage differentiation. However, the inhibitory effect of ROS elimination on macrophage differentiation is overcome when cells are polarized to classically activated (M1), but not M2, macrophages. More importantly, the continuous administration of the ROS inhibitor BHA efficiently blocked the occurrence of TAMs and markedly suppressed tumorigenesis in mouse cancer models. Targeting TAMs by blocking ROS can be a potentially effective method for cancer treatment. PMID:23752925

Zhang, Yan; Choksi, Swati; Chen, Kun; Pobezinskaya, Yelena; Linnoila, Ilona; Liu, Zheng-Gang

2013-01-01

96

Dysregulation of Macrophage Activation Profiles by Engineered Nanoparticles  

SciTech Connect

Although the potential human health impacts from exposure to engineered nanoparticles (ENPs) are uncertain, past epidemiological studies have established correlations between exposure to ambient air pollution particulates and the incidence of pneumonia and lung infections. Using amorphous silica and superparamagnetic iron oxide (SPIO) as model high production volume ENPs, we examined how macrophage activation by bacterial lipopolysaccharide (LPS) or the lung pathogen Streptococcus pneumoniae is altered by ENP pre-treatment. Neither silica nor SPIO treatment elicited direct cytotoxic or pro-inflammatory effects in bone marrow-derived macrophages. However, pre-treatment of macrophages with SPIO caused extensive reprogramming of nearly 500 genes regulated in response to LPS challenge, hallmarked by exaggerated activation of oxidative stress response pathways and suppressed activation of both pro- and anti-inflammatory pathways. Silica pre-treatment altered regulation of only 67 genes, but there was strong correlation with gene sets affected by SPIO. Macrophages exposed to SPIO displayed a phenotype suggesting an impaired ability to transition from a M1 to M2-like activation state, characterized by suppressed IL-10 induction, enhanced TNF? production, and diminished phagocytic activity toward S. pneumoniae. Studies in macrophages deficient in scavenger receptor A (SR-A) showed SR-A participates in cell uptake of both the ENPs and S. pneumonia, and co-regulates the anti-inflammatory IL-10 pathway. Thus, mechanisms for dysregulation of innate immunity exist by virtue that common receptor recognition pathways are used by some ENPs and pathogenic bacteria, although the extent of transcriptional reprogramming of macrophage function depends on the physicochemical properties of the ENP after internalization. Our results also illustrate that biological effects of ENPs may be indirectly manifested only after challenging normal cell function. Nanotoxicology screening strategies should therefore consider how exposure to these materials alters susceptibility to other environmental exposures.

Kodali, Vamsi K.; Littke, Matt H.; Tilton, Susan C.; Teeguarden, Justin G.; Shi, Liang; Frevert, Charles W.; Wang, Wei; Pounds, Joel G.; Thrall, Brian D.

2013-07-09

97

Dysregulation of Macrophage Activation Profiles by Engineered Nanoparticles  

PubMed Central

Although the potential human health impacts from exposure to engineered nanoparticles (ENPs) are uncertain, past epidemiological studies have established correlations between exposure to ambient air pollution particulates and the incidence of pneumonia and lung infections. Using amorphous silica and superparamagnetic iron oxide (SPIO) as model high production volume ENPs, we examined how macrophage activation by bacterial lipopolysaccharide (LPS) or the lung pathogen Streptococcus pneumoniae is altered by ENP pre-treatment. Neither silica nor SPIO treatment elicited direct cytotoxic or pro-inflammatory effects in bone marrow-derived macrophages. However, pre-treatment of macrophages with SPIO caused extensive reprogramming of nearly 500 genes regulated in response to LPS challenge, hallmarked by exaggerated activation of oxidative stress response pathways and suppressed activation of both pro- and anti-inflammatory pathways. Silica pre-treatment altered regulation of only 67 genes, but there was strong correlation with gene sets affected by SPIO. Macrophages exposed to SPIO displayed a phenotype suggesting an impaired ability to transition from a M1 to M2-like activation state, characterized by suppressed IL-10 induction, enhanced TNF? production, and diminished phagocytic activity toward S. pneumoniae. Studies in macrophages deficient in scavenger receptor A (SR-A) showed SR-A participates in cell uptake of both the ENPs and S. pneumonia, and co-regulates the anti-inflammatory IL-10 pathway. Thus, mechanisms for dysregulation of innate immunity exist by virtue that common receptor recognition pathways are used by some ENPs and pathogenic bacteria, although the extent of transcriptional reprogramming of macrophage function depends on the physicochemical properties of the ENP after internalization. Our results also illustrate that biological effects of ENPs may be indirectly manifested only after challenging normal cell function. Nanotoxicology screening strategies should therefore consider how exposure to these materials alters susceptibility to other environmental exposures. PMID:23808590

Kodali, Vamsi; Littke, Matthew H.; Tilton, Susan C.; Teeguarden, Justin G.; Shi, Liang; Frevert, Charles W.; Wang, Wei; Pounds, Joel G.; Thrall, Brian D.

2013-01-01

98

Innate immunity and monocyte-macrophage activation in atherosclerosis  

PubMed Central

Innate inflammation is a hallmark of both experimental and human atherosclerosis. The predominant innate immune cell in the atherosclerotic plaque is the monocyte-macrophage. The behaviour of this cell type within the plaque is heterogeneous and depends on the recruitment of diverse monocyte subsets. Furthermore, the plaque microenvironment offers polarisation and activation signals which impact on phenotype. Microenvironmental signals are sensed through pattern recognition receptors, including toll-like and NOD-like receptors - the latter of which are components of the inflammasome - thus dictating macrophage behaviour and outcome in atherosclerosis. Recently cholesterol crystals and modified lipoproteins have been recognised as able to directly engage these pattern recognition receptors. The convergent role of such pathways in terms of macrophage activation is discussed in this review. PMID:21526997

2011-01-01

99

Efficacy of oral administration of heat-killed probiotics from Mongolian dairy products against influenza infection in mice: Alleviation of influenza infection by its immunomodulatory activity through intestinal immunity  

Microsoft Academic Search

Some probiotics possess immunomodulatory activities and have been used as complementary and alternative medicines. We previously found that 10 lactic acid bacteria (LAB) strains isolated from traditional Mongolian dairy products showed probiotic potential in vitro. In this study, we assessed the immunomodulatory activity of 10 LABs on influenza virus (IFV) infection in relation to their efficacies in IFV-infected mice. In

Shiro Takeda; Masahiko Takeshita; Yukiharu Kikuchi; Bumbein Dashnyam; Satoshi Kawahara; Hiroki Yoshida; Wataru Watanabe; Michio Muguruma; Masahiko Kurokawa

100

Apoptosis-Inducing Activity of Clofazimine in Macrophages?  

PubMed Central

Clofazimine is a riminophenazine compound which has been used for the treatment of leprosy since the 1960s. Although the drug is effective in the management of leprosy reactions because of its anti-inflammatory activity, the mechanism leading to the cessation of inflammation is not well understood. In the present study, it was shown that clofazimine exhibits apoptosis-inducing activity in macrophages. When human monocyte-derived macrophages were cultured in vitro in the presence of clofazimine, the cells exhibited a marked decrease in metabolic activity and showed shrinkage in cell size, indicating cell death. Nuclear condensation and fragmentation were also observed by Giemsa and Hoechst 33248 stains. The endonuclease inhibitor ZnCl2 inhibited the clofazimine-induced cell death. Significant enhancement of caspase-3 activity was observed in clofazimine-treated macrophages and THP-1 cells. Collectively, these results suggest the apoptosis-inducing activity of clofazimine in macrophages, which may also be responsible for the antibacterial properties of clofazimine. PMID:21690278

Fukutomi, Yasuo; Maeda, Yumi; Makino, Masahiko

2011-01-01

101

Activation and increment of alveolar macrophages induced by nitrogen dioxide  

SciTech Connect

Male Wistar rats were exposed to 4 ppm nitrogen dioxide (NO/sub 2/) for 10 d, and at intervals alveolar macrophages were collected by pulmonary lavage. A metabolic enhancement of alveolar macrophages was observed on d 4 of exposure. The specific activities of glucose-6-phosphate dehydrogenase and glutathione peroxidase of the peroxidative metabolic pathway increased to 1.29-fold and 1.17-fold those of the control values, respectively. The specific activities of succinate-cytochrome c reductase of the mitochondrial respiratory system and pyruvate kinase of the glycolytic pathway also increased to 1.17-fold and 1.20-fold those of the control values, respectively. In addition, the incorporation of (/sup 3/H)leucine and (/sup 14/C)thymidine into alveolar macrophages were elevated to 1.77-fold and 1.84-fold those of the control values, respectively. The activities of all enzymes tested decreased to control levels by d 10. The number of alveolar macrophages collected from exposed animals increased to 1.24-fold that of the control value of d 7 and was maintained at a significantly higher level until d 10. Alveolar macrophages were heterogeneous in size (7-21 ..mu..m in diameter), and most of them were distributed between 11 and 17 ..mu..m in diameter. Exposures to 4 ppm NO/sub 2/ increased significantly the cells of 9-13 ..mu..m in diameter on the seventh day. These results show that exposures to 4 ppm NO/sub 2/ cause a metabolic enhancement and subsequent increase in alveolar macrophages.

Mochitate, K.; Takahashi, Y.; Ohsumi, T.; Miura, T.

1986-01-01

102

Oxygen tension limits nitric oxide synthesis by activated macrophages.  

PubMed Central

Previous studies have established that constitutive calcium-dependent ('low-output') nitric oxide synthase (NOS) is regulated by oxygen tension. We have investigated the role of oxygen tension in the synthesis of NO by the 'high-output' calcium-independent NOS in activated macrophages. Hypoxia increased macrophage NOS gene expression in the presence of one additional activator, such as lipopolysaccharide or interferon-gamma, but not in the presence of both. Hypoxia markedly reduced the synthesis of NO by activated macrophages (as measured by accumulation of nitrite and citrulline), such that, at 1% oxygen tension, NO accumulation was reduced by 80-90%. The apparent K(m) for oxygen calculated from cells exposed to a range of oxygen tensions was found to be 10.8%, or 137 microM, O(2) This value is considerably higher than the oxygen tension in tissues, and is virtually identical to that reported recently for purified recombinant macrophage NOS. The decrease in NO synthesis did not appear to be due to diminished arginine or cofactor availability, since arginine transport and NO synthesis during recovery in normoxia were normal. Analysis of NO synthesis during hypoxia as a function of extracellular arginine indicated that an altered V(max), but not K(m)(Arg), accounted for the observed decrease in NO synthesis. We conclude that oxygen tension regulates the synthesis of NO in macrophages by a mechanism similar to that described previously for the calcium-dependent low-output NOS. Our data suggest that oxygen tension may be an important physiological regulator of macrophage NO synthesis in vivo. PMID:10970783

McCormick, C C; Li, W P; Calero, M

2000-01-01

103

Dopamine Receptor Activation Increases HIV Entry into Primary Human Macrophages  

PubMed Central

Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers. PMID:25268786

Gaskill, Peter J.; Yano, Hideaki H.; Kalpana, Ganjam V.; Javitch, Jonathan A.; Berman, Joan W.

2014-01-01

104

Dopamine Receptor Activation Increases HIV Entry into Primary Human Macrophages.  

PubMed

Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers. PMID:25268786

Gaskill, Peter J; Yano, Hideaki H; Kalpana, Ganjam V; Javitch, Jonathan A; Berman, Joan W

2014-01-01

105

Studies on the immunomodulatory effects of Ashwagandha  

Microsoft Academic Search

The immunomodulatory activity of an Indian Ayurvedic medicinal preparation, Ashwagandna (Withania somnifera (L. Dunal)) was studied in mice with myelosuppression induced by one or more of the following three compounds: cyclophosphamide, azathioprin, or prednisolone. The assessment of immunomodulatory activity was carried out by hematological and serological tests. A significant modulation of immune reactivity was observed in all the three animal

Mohammed Ziauddin; Neeta Phansalkar; Pralhad Patki; Sham Diwanay; Bhushan Patwardhan

1996-01-01

106

Rainbow trout macrophages in vitro: morphology and phagocytic activity.  

PubMed

The properties of macrophages from the pronephros of Rainbow trout (Salmo gairdneri Richardson) were studied in vitro. We found that phagocytes obtained from the pronephros constitute a non-homogeneous cell population. Three populations with different adherence properties were examined with special emphasis on morphology and phagocytic capacity. The differentiation of the three populations in culture was similar morphologically, and their phagocytic activity showed only small variations. The methods for cell separation and culture reported here are a useful tool for gaining better understanding of how Rainbow trout macrophages function in the immune response. PMID:7095232

Braun-Nesje, R; Kaplan, G; Seljelid, R

1982-01-01

107

Diet Modifies the Neuroimmune System by Influencing Macrophage Activation  

ERIC Educational Resources Information Center

It has long been appreciated that adequate nutrition is required for proper immune function and it is now recognized that dietary components contribute to modulation of immune cells, subsequently impacting the whole body's response during an immune challenge. Macrophage activation plays a critical role in the immune system and directs the…

Sherry, Christina Lynn

2009-01-01

108

Attenuated Activation of Macrophage TLR9 by DNA from Virulent Mycobacteria  

Microsoft Academic Search

Alveolar macrophages are the first line of host defence against mycobacteria, but an insufficient host response allows survival of bacteria within macrophages. We aimed to investigate the role of Toll-like receptor 9 (TLR9) activation in macrophage defence against mycobacteria. Human in vitrodifferentiated macrophages as well as human and mouse alveolar macrophages showed TLR9 mRNA and protein expression. The cells were

Alexandra K. Kiemer; Ryan H. Senaratne; Jessica Hoppstädter; Britta Diesel; Lee W. Riley; Koichi Tabeta; Stefan Bauer; Bruce Beutler; Bruce L. Zuraw

2009-01-01

109

Potentiation of macrophage activity by thymol through augmenting phagocytosis.  

PubMed

The potent role of thymol, a natural compound, in modulation of macrophage activity was evaluated by determining all the sequential steps involved during phagocytosis. We found a significant increase in the proliferation of splenocytes in the presence of thymol and it proved to be a good mitogen. Uptake capacity of macrophages was enhanced due to increased membrane fluidity after treatment with thymol and it also increases lysosomal activity of macrophages. Data of superoxide anion generation revealed the involvement of thymol in the generation of respiratory burst as it potentiated this property of macrophages at a concentration of 150 ?M. In the case of TNF-?, IL-1ß and PGE(2) a decreased level of secretion was observed 154 ?g/ml, 736.1 ?g/ml, and 151 ?g/ml respectively when compared with lipopolysaccharide treated cells, where the level of these cytokines was significantly high. We also determined the anti-complementary activity of thymol which showed to be more effective than rosmarinic acid. Thus, the results obtained from the study suggest the potential role of thymol as a natural immunostimulatory drug which can be used in the treatment of various immunological disorders. PMID:24316253

Chauhan, Anil Kumar; Jakhar, Rekha; Paul, Souren; Kang, Sun Chul

2014-02-01

110

Immunomodulatory activity of geranial, geranial acetate, gingerol, and eugenol essential oils: evidence for humoral and cell-mediated responses  

PubMed Central

Objective: The immunomodulatory effect of geranial, geranial acetate, gingerol, and eugenol essential oils were evaluated by studying humoral and cell-mediated immune responses. Materials and Method: The essential oils were evaluated for immunomodulatory activity in in vivo studies, using rats as the animal model. The essential oils were tested for hypersensitivity and hemagglutination reactions, using sheep red blood cells (SRBC) as the antigen while sodium carboxy methyl cellulose (SCMC) served as the control in all the tests. Result: Orally administrated essential oils showed a significant increase of test parameters, viz., haemagglutinating antibody titre (HAT) and delayed type hypersensitivity (DTH) response. In rats immunized with sheep RBC, essential oils enhanced the humoral antibody response to the antigen and significantly potentiated the cellular immunity by facilitating the foot pad thickness response to sheep RBC in sensitized rats with doses of 50-800 mg/ml. Haemagglutination titre of geraniol showed the highest increase of 139.3±6.38 and with 5.9±0.7 DTH, respectively. For geranial acetate, the haemagglutination titre showed a moderate increase of 87.5±5.9 and highest increase in DTH with 5.9±0.8, respectively. Using gingerol, the haemagglutination titre showed a moderate increase with 88.2±6.306 and DTH 3.5±0.5, respectively and for eugenol, the haemaggulation titre showed a moderate increase with 112.06±6.169 and DTH 4.4±0.6, respectively. These differences were statistically significant. Conclusion: The essential oils were found to have a significant immunostimulant activity on both the specific and non-specific immune mechanisms. PMID:25050278

Farhath, Seema; Vijaya, PP; Vimal, Manivannan

2013-01-01

111

Macrophages make me sick: how macrophage activation states influence sickness behavior  

PubMed Central

Summary The macrophage (M?) is an essential cellular first responder in the innate immune system, sensing, alerting, removing and destroying intrinsic and extrinsic pathogens. While congenital aplasia of granulocytes, T or B lymphocytes leads to serious disease, lack of M?s is incompatible with life. The M?, however, is not a monomorphic entity. These constructers, repairers and defenders of the body are diverse in form and function. What controls M? phenotype is beginning to be understood and involves a complex interplay of origination, location and microenvironment. Common to all M? developmental pathways are pro-inflammatory and anti-inflammatory cytokines. M?s respond to these bioactives in distinct ways developing recently recognized activation phenotypes that canonically support bacterial clearance (classical activation), parasite defense/tissue repair (alternative activation) and anti-inflammation (deactivation). Critically, the same cytokines which orchestrate immune defense and homeostasis dramatically impact sense of well being and cognition by eliciting sickness symptoms. Such behaviors are the manifestation of pro/anti-inflammatory cytokine action in the brain and are a direct consequence of M? function. This review describes the “new” archetypal M? activation states, delineates microglia phenotypic plasticity and explores the importance of these macrophage activation states to sickness behavior. PMID:21855222

Moon, Morgan L.; McNeil, Leslie K.; Freund, Gregory G.

2011-01-01

112

Crosstalk between circadian rhythmicity, mitochondrial dynamics and macrophage bactericidal activity.  

PubMed

Biological functions show rhythmic fluctuations with 24-hr periodicity regulated by circadian proteins encoded by the so-called 'clock' genes. The absence or deregulation of circadian proteins in mice leads to metabolic disorders and in vitro models have shown that the synthesis of pro-inflammatory cytokines by macrophages follows a circadian rhythm so showing a link between circadian rhythmicity, metabolism and immunity. Recent evidence reveals that mitochondrial shape, position and size, collectively referred to as mitochondrial dynamics, are related to both cell metabolism and immune function. However, studies addressing the simultaneous crosstalk between circadian rhythm, mitochondrial dynamics and cell immune function are scarce. Here, by using an in vitro model of synchronized murine peritoneal macrophages, we present evidence that the mitochondrial dynamics and the mitochondrial membrane potential (??m ) follow a circadian rhythmic pattern. In addition, it is shown that the fusion of mitochondria along with high ??m , indicative of high mitochondrial activity, precede the highest phagocytic and bactericidal activity of macrophages on Salmonella typhimurium. Taken together, our results suggest a timely coordination between circadian rhythmicity, mitochondrial dynamics, and the bactericidal capacity of macrophages. PMID:24903615

Oliva-Ramírez, Jacqueline; Moreno-Altamirano, María Maximina B; Pineda-Olvera, Benjamín; Cauich-Sánchez, Patricia; Sánchez-García, F Javier

2014-11-01

113

Characteristics of Suppressor Macrophages Induced by Mycobacterial and Protozoal Infections in relation to Alternatively Activated M2 Macrophages  

PubMed Central

In the advanced stages of mycobacterial infections, host immune systems tend to change from a Th1-type to Th2-type immune response, resulting in the abrogation of Th1 cell- and macrophage-mediated antimicrobial host protective immunity. Notably, this type of immune conversion is occasionally associated with the generation of certain types of suppressor macrophage populations. During the course of Mycobacterium tuberculosis (MTB) and Mycobacterium avium-intracellulare complex (MAC) infections, the generation of macrophages which possess strong suppressor activity against host T- and B-cell functions is frequently encountered. This paper describes the immunological properties of M1- and M2-type macrophages generated in tumor-bearing animals and those generated in hosts with certain microbial infections. In addition, this paper highlights the immunological and molecular biological characteristics of suppressor macrophages generated in hosts with mycobacterial infections, especially MAC infection. PMID:22666284

Tomioka, Haruaki; Tatano, Yutaka; Maw, Win Win; Sano, Chiaki; Kanehiro, Yuichi; Shimizu, Toshiaki

2012-01-01

114

Efficacy of oral administration of heat-killed probiotics from Mongolian dairy products against influenza infection in mice: alleviation of influenza infection by its immunomodulatory activity through intestinal immunity.  

PubMed

Some probiotics possess immunomodulatory activities and have been used as complementary and alternative medicines. We previously found that 10 lactic acid bacteria (LAB) strains isolated from traditional Mongolian dairy products showed probiotic potential in vitro. In this study, we assessed the immunomodulatory activity of 10 LABs on influenza virus (IFV) infection in relation to their efficacies in IFV-infected mice. In an intranasal IFV infection model in mice, oral administration of boiled Lactobacillus plantarum 06CC2 strain (20mg/mouse), one of the 10 LABs, twice daily for 10 days starting two days before infection was significantly effective in protecting the body weight loss of infected mice, reducing virus yields in the lungs on days 2, 4, and 6 after infection, and prolonging survival times without toxicity. The total numbers of infiltrated cells in the bronchoalveolar lavage fluid (BALF), especially macrophages and neutrophils, were significantly reduced by 06CC2 administration on day 2. On day 2, tumor necrosis factor (TNF)-? production in BALF was also reduced significantly, but interferon-?, interleukin-12, and interferon-? productions were augmented and natural killer (NK) cell activity was significantly elevated. Furthermore, the gene expressions of interleukin-12 receptor and interferon-? in Peyer's patches were augmented by 06CC2 administration on day 2. Thus, 06CC2 was suggested to alleviate influenza symptoms in mice in correlation with the augmentation of NK cell activity associated with the enhancement of interferon-? and Th1 cytokine productions through intestinal immunity and the reduction of TNF-? in the early stage of infection. PMID:21871585

Takeda, Shiro; Takeshita, Masahiko; Kikuchi, Yukiharu; Dashnyam, Bumbein; Kawahara, Satoshi; Yoshida, Hiroki; Watanabe, Wataru; Muguruma, Michio; Kurokawa, Masahiko

2011-12-01

115

Alternatively activated macrophages derived from monocytes and tissue macrophages are phenotypically and functionally distinct.  

PubMed

Macrophages adopt an alternatively activated phenotype (AAMs) when activated by the interleukin-4receptor(R)?. AAMs can be derived either from proliferation of tissue resident macrophages or recruited inflammatory monocytes, but it is not known whether these different sources generate AAMs that are phenotypically and functionally distinct. By transcriptional profiling analysis, we show here that, although both monocyte and tissue-derived AAMs expressed high levels of Arg1, Chi3l3, and Retnla, only monocyte-derived AAMs up-regulated Raldh2 and PD-L2. Monocyte-derived AAMs were also CX3CR1-green fluorescent protein (GFP)(high) and expressed CD206, whereas tissue-derived AAMs were CX3CR1-GFP and CD206 negative. Monocyte-derived AAMs had high levels of aldehyde dehydrogenase activity and promoted the differentiation of FoxP3(+) cells from naïve CD4(+) cells via production of retinoic acid. In contrast, tissue-derived AAMs expressed high levels of uncoupling protein 1. Hence monocyte-derived AAM have properties associated with immune regulation, and the different physiological properties associated with AAM function may depend on the distinct lineage of these cells. PMID:24695852

Gundra, Uma Mahesh; Girgis, Natasha M; Ruckerl, Dominik; Jenkins, Stephen; Ward, Lauren N; Kurtz, Zachary D; Wiens, Kirsten E; Tang, Mei San; Basu-Roy, Upal; Mansukhani, Alka; Allen, Judith E; Loke, P'ng

2014-05-15

116

Immunomodulatory activity of thunberginol A and related compounds isolated from Hydrangeae Dulcis Folium on splenocyte proliferation activated by mitogens.  

PubMed

We investigated the immunomodulatory effects of antiallergic constituents from Hydrangeae Dulcis Folium, the processed leaves of Hydrangea macrophylla SERINGE var. thunbergii MAKINO, on splenocyte proliferation in mice. Thunberginol A and hydrangenol significantly suppressed T lymphocyte proliferation induced by concanavalin A. Thunberginol A also suppressed B lymphocyte proliferation induced by lipopolysaccharide, but other constituents induced significant increases. These inhibitory effects of thunberginol A on splenocyte proliferation seemed to contribute to the suppressive effect on type IV allergy. PMID:9871657

Matsuda, H; Shimoda, H; Yamahara, J; Yoshikawa, M

1998-02-01

117

Immunomodulatory activity of butanol fraction of Gentiana olivieri Griseb. on Balb/C mice  

PubMed Central

Objective To explore the immunomodulatory properties of 80% ethanol extract and butanol fraction of Gentiana olivieri (G. olivieri) Griseb on Balb/C mice. Methods The study was performed with basic models of immunomodulation such as the humoral antibody response (hemoglutination antibody titres), cell mediated immune response (delayed type hypersensitivity and in vivo carbon clearance or phagocytosis). Ethanol (80%) extract of flowering aerial parts of G. olivieri and its butanol fraction were administered p.o. (orally) to the mice. Levamisole, 2.5 mg/kg was used as standard drug. Results There was a potentiation of immune response to sheep red blood cells by cellular and humoral mediated mechanisms comparable to levamisole (2.5 mg/kg) by both 80% ethanol extract and the butanol fraction at doses of 50-200 mg/kg in male Balb/C mice. Both significantly (P<0.01) potentiated the humoral immune response in cyclophosphamide (250 mg/kg) immunosupressed mice at 100 and 200 mg/kg of each extract and fraction as compared to control. The potentiation of delayed type hypersensitivity response was statistically significant (P<0.01) at 200 mg/kg of ethanol extract and 100, 200 mg/kg of butanol fraction as compared to control. The phagocytosis was significant at 200 mg/kg with butanol fraction of G. olivieri. Conclusions The results reveal the immunostimulant effects of plant G. olivieri in mice by acting through cellular and humoral immunity in experimental models of immunity in mice. Butanol fraction is the most effective at a dose level of 200 mg/kg. PMID:23569945

Singh, Satnam; CPS, Yadav; Noolvi, Malleshappa N

2012-01-01

118

GABAergic activities enhance macrophage inflammatory protein-1? release from microglia (brain macrophages) in postnatal mouse brain  

PubMed Central

Microglial cells (brain macrophages) invade the brain during embryonic and early postnatal development, migrate preferentially along fibre tracts to their final position and transform from an amoeboid to a ramified morphology. Signals by which the invading microglia communicate with other brain cells are largely unknown. Here, we studied amoeboid microglia in postnatal corpus callosum obtained from 6- to 8-day-old mice. These cells accumulated on the surface of acute brain slices. Whole-cell patch-clamp recordings revealed that the specific GABAA receptor agonist muscimol triggered a transient increase in conductance typical for inward rectifying potassium channels in microglia. This current increase was not mediated by microglial GABAA receptors since microglial cells removed from the slice surface no longer reacted and cultured microglia only responded when a brain slice was placed in their close vicinity. Muscimol triggered a transient increase in extracellular potassium concentration ([K+]o) in brain slices and an experimental elevation of [K+]o mimicked the muscimol response in microglial cells. Moreover, in adult brain slices, muscimol led only to a minute increase in [K+]o and microglial cells failed to respond to muscimol. In turn, an increase in [K+]o stimulated the release of chemokine macrophage inflammatory protein-1? (MIP1-?) from brain slices and from cultures of microglia but not astrocytes. Our observations indicate that invading microglia in early postnatal development sense GABAergic activities indirectly via sensing changes in [K+]o which results in an increase in MIP1-? release. PMID:19047202

Cheung, Giselle; Kann, Oliver; Kohsaka, Shinichi; Faerber, Katrin; Kettenmann, Helmut

2009-01-01

119

Synthesis and pharmacological evaluation of polyfunctional benzimidazole-NSAID chimeric molecules combining anti-inflammatory, immunomodulatory and antioxidant activities.  

PubMed

Polyfunctional compounds comprise a novel class of therapeutic agents for treatment of multifactorial diseases. The present study reports a series of benzimidazole-non-steroidal anti-inflammatory drugs (NSAIDs) conjugates (1-10) as novel polyfunctional compounds synthesized in the presence of orthophosphoric acid. The compounds were evaluated for anti-inflammatory (carageenan-induced paw edema model), immunomodulatory (direct haemagglutination test and carbon clearance index models), antioxidant (in vitro and in vivo) and for ulcerogenic effects. Each of the compound has retained the anti-inflammatory activity of the corresponding parent NSAID while exhibiting significantly reduced gastric ulcers. Additionally, the compounds are found to possess potent immunostimulatory and antioxidant activities. The compound 8 was maximally potent (antibody titre value 358.4 ± 140.21, carbon clearance index 0.053 ± 0.002 and antioxidant EC50 value 0.03 ± 0.006). These compounds, exhibiting such multiple pharmacological activities, can be taken as lead for the development of potent drugs for the treatment of chronic multifactorial diseases involving inflammation, immune system modulation and oxidative stress such as cancers. The Lipinski's parameters suggested the compounds to be bear drug like properties. PMID:24190755

Bansal, Yogita; Silakari, Om

2014-11-01

120

Delineation of Diverse Macrophage Activation Programs in Response to Intracellular Parasites and Cytokines  

PubMed Central

Background The ability to reside and proliferate in macrophages is characteristic of several infectious agents that are of major importance to public health, including the intracellular parasites Trypanosoma cruzi (the etiological agent of Chagas disease) and Leishmania species (etiological agents of Kala-Azar and cutaneous leishmaniasis). Although recent studies have elucidated some of the ways macrophages respond to these pathogens, the relationships between activation programs elicited by these pathogens and the macrophage activation programs elicited by bacterial pathogens and cytokines have not been delineated. Methodology/Principal Findings To provide a global perspective on the relationships between macrophage activation programs and to understand how certain pathogens circumvent them, we used transcriptional profiling by genome-wide microarray analysis to compare the responses of mouse macrophages following exposure to the intracellular parasites T. cruzi and Leishmania mexicana, the bacterial product lipopolysaccharide (LPS), and the cytokines IFNG, TNF, IFNB, IL-4, IL-10, and IL-17. We found that LPS induced a classical activation state that resembled macrophage stimulation by the Th1 cytokines IFNG and TNF. However, infection by the protozoan pathogen L. mexicana produced so few transcriptional changes that the infected macrophages were almost indistinguishable from uninfected cells. T. cruzi activated macrophages produced a transcriptional signature characterized by the induction of interferon-stimulated genes by 24 h post-infection. Despite this delayed IFN response by T. cruzi, the transcriptional response of macrophages infected by the kinetoplastid pathogens more closely resembled the transcriptional response of macrophages stimulated by the cytokines IL-4, IL-10, and IL-17 than macrophages stimulated by Th1 cytokines. Conclusions/Significance This study provides global gene expression data for a diverse set of biologically significant pathogens and cytokines and identifies the relationships between macrophage activation states induced by these stimuli. By comparing macrophage activation programs to pathogens and cytokines under identical experimental conditions, we provide new insights into how macrophage responses to kinetoplastids correlate with the overall range of macrophage activation states. PMID:20361029

Zhang, Shuyi; Kim, Charles C.; Batra, Sajeev; McKerrow, James H.; Loke, P'ng

2010-01-01

121

Induction of macrophage antitumor activity by gamma radiation  

SciTech Connect

The authors have developed a model system for examination of macrophage-mediated tumor cells lysis, using the murine macrophage tumor cell line RAW 264.7. These cells, like normal macrophages, exhibit a strict requirement for interaction with both interferon-..gamma.. (IFN-..gamma.., the priming signal) and bacterial lipopolysaccharide (LPS, the triggering signal) in the development of tumor cytolytic activity. In this system, the priming effects of IFN-..gamma.. decay rapidly following withdrawal of this mediator and the cells become unresponsive to LPS. They have recently observed that gamma radiation of the RAW 264.7 cells results in development of a primed state which is stable and responsive to LPS triggering for a least 48 hours. Irradiation-induced development of the primed phenotype is not solely the result of cytostatic effects as LPS treatment alone results in marked decreases in /sup 3/H-TdR incorporation in the absence of cytolytic potential. In addition to delivering the priming signal for tumor cytotoxicity, irradiation of this cell line results in changes in cell morphology that are typical of activation. Finally, treatment with irradiation results in increased cell surface expression of MHC-encoded Class I antigens; however, Class II antigen expression is not induced. Thus, the effects of gamma radiation on this cell line are strikingly similar to those resulting from incubation with IFN-..gamma...

Lambert, L.; Paulnock, D.M.

1986-03-05

122

Induction of antitumor activity in macrophages by mycoplasmas in concert with interferon  

Microsoft Academic Search

Summary The in vitro growth of tumor cells infected with mycoplasmas was suppressed by macrophages pretreated with interferon (IFN), but the growth of mycoplasma-free tumor cells was not suppressed. Pretreatment of macrophages with IFN plus mycoplasmas or their soluble factors either simultaneously or sequentially, IFN first and mycoplasmas second, but not in the reverse order, was effective in activating macrophages

Kazuko Uno; Morio Takema; Shigetaka Hidaka; Reishi Tanaka; Takao Konishi; Takuma Kato; Shinji Nakamura; Shigeru Muramatsu

1990-01-01

123

Attenuated activation of macrophage TLR9 by DNA from virulent mycobacteria.  

PubMed

Alveolar macrophages are the first line of host defence against mycobacteria, but an insufficient host response allows survival of bacteria within macrophages. We aimed to investigate the role of Toll-like receptor 9 (TLR9) activation in macrophage defence against mycobacteria. Human in vitro differentiated macrophages as well as human and mouse alveolar macrophages showed TLR9 mRNA and protein expression. The cells were markedly activated by DNA isolated from attenuated mycobacterial strains (H37Ra and Mycobacterium bovis BCG) as assessed by measuring cytokine expression by real-time PCR, whereas synthetic phosphorothioate-modified oligonucleotides had a much lower potency to activate human macrophages. Intracellular replication of H37Ra was higher in macrophages isolated from TLR9-deficient mice than in macrophages from wild-type mice, whereas H37Rv showed equal survival in cells from wild-type or mutant mice. Increased bacterial survival in mouse macrophages was accompanied by altered cytokine production as determined by Luminex bead assays. In vivo infection experiments also showed differential cytokine production in TLR9-deficient mice compared to wild-type animals. Both human monocyte-derived macrophages as well as human alveolar macrophages showed reduced activation upon treatment with DNA isolated from bacteria from virulent (M. bovis and H37Rv) compared to attenuated mycobacteria. We suggest attenuated TLR9 activation contributes to the insufficient host response against virulent mycobacteria. PMID:20375564

Kiemer, Alexandra K; Senaratne, Ryan H; Hoppstädter, Jessica; Diesel, Britta; Riley, Lee W; Tabeta, Koichi; Bauer, Stefan; Beutler, Bruce; Zuraw, Bruce L

2009-01-01

124

PSP activates monocytes in resting human peripheral blood mononuclear cells: immunomodulatory implications for cancer treatment.  

PubMed

Polysaccharopeptide (PSP), from Coriolus versicolor, has been used as an adjuvant to chemotherapy, and has demonstrated anti-tumor and immunomodulating effects. However its mechanism remains unknown. To elucidate how PSP affects immune populations, we compared PSP treatments both with and without prior incubation in phytohaemagglutinin (PHA) - a process commonly used in immune population experimentation. We first standardised a capillary electrophoresis fingerprinting technique for PSP identification and characterisation. We then established the proliferative capability of PSP on various immune populations in peripheral blood mononuclear cells, using flow cytometry, without prior PHA treatment. It was found that PSP significantly increased the number of monocytes (CD14(+)/CD16(-)) compared to controls without PHA. This increase in monocytes was confirmed using another antibody panel of CD14 and MHCII. In contrast, proliferations of T-cells, NK, and B-cells were not significantly changed by PSP. Thus, stimulating monocyte/macrophage function with PSP could be an effective therapeutic intervention in targeting tumors. PMID:23497877

Sekhon, Bhagwant Kaur; Sze, Daniel Man-Yuen; Chan, Wing Keung; Fan, Kei; Li, George Qian; Moore, Douglas Edwin; Roubin, Rebecca Heidi

2013-06-15

125

Recombinant Expression of a Novel Fungal Immunomodulatory Protein with Human Tumor Cell Antiproliferative Activity from Nectria haematococca  

PubMed Central

To our best knowledge, all of the fungal immunomodulatory proteins (FIPs) have been successfully extracted and identified in Basidomycetes, with only the exception of FIP from ascomycete Nectria haematococca (FIP-nha) discovered through homology alignment most recently. In this work, a gene encoding FIP-nha was synthesized and recombinantly expressed in an Escherichia coli expression system. SDS-PAGE and MALDI-MS analyses of recombinant FIP-nha (rFIP-nha) indicated that the gene was successfully expressed. The yield of the bioactive FIP-nha protein was 42.7 mg/L. In vitro assays of biological activity indicated that the rFIP-nha caused hemagglutination of human and rabbit red blood cells, significantly stimulated mouse spleen lymphocyte proliferation, and enhanced expression of interleukin-2 (IL-2) released from mouse splenocytes, revealing a strong antitumor effect against HL60, HepG2 and MGC823. Through this work, we constructed a rapid and efficient method of FIP production, and suggested that FIP-nha is a valuable candidate for use in future medical care and pharmaceutical products. PMID:25272229

Li, Shuying; Nie, Ying; Ding, Yang; Shi, Lijun; Tang, Xuanming

2014-01-01

126

Lectin coated MgO nanoparticle: its toxicity, antileishmanial activity, and macrophage activation.  

PubMed

The purpose of this research was to evaluate toxicity of uncoated magnesium oxide nanoparticles (MgO NPs), MgO NPs coated with Peanut agglutinin (PNA) lectin, and PNA alone on the promastigotes of Leishmania major (L. major) and macrophages of BALB/c mice. On the other hand, antileishmanial property of uncoated MgO NPs, lectin coated MgO NPs, and PNA lectin alone was evaluated, and also macrophage activation was investigated after treatment with these materials by measurement of nitrite, H2O2, and some interleukins. This study showed that PNA lectin and lectin coated MgO NPs had approximately no toxicity on L. major and macrophages, but some toxic effects were observed for uncoated MgO NPs, especially at concentration of 500?µg/mL. Interestingly, lectin coated MgO NPs had the highest antileishmanial activity and macrophage activation, compared with uncoated MgO NPs and PNA lectin. PMID:24393043

Jebali, Ali; Hekmatimoghaddam, Seyedhossein; Kazemi, Bahram; Allaveisie, Azra; Masoudi, Alireza; Daliri, Karim; Sedighi, Najme; Ranjbari, Javad

2014-10-01

127

Spherical Lactic Acid Bacteria Activate Plasmacytoid Dendritic Cells Immunomodulatory Function via TLR9-Dependent Crosstalk with Myeloid Dendritic Cells  

PubMed Central

Plasmacytoid dendritic cells (pDC) are a specialized sensor of viral and bacterial nucleic acids and a major producer of IFN-? that promotes host defense by priming both innate and acquired immune responses. Although synthetic Toll-like receptor (TLR) ligands, pathogenic bacteria and viruses activate pDC, there is limited investigation of non-pathogenic microbiota that are in wide industrial dietary use, such as lactic acid bacteria (LAB). In this study, we screened for LAB strains, which induce pDC activation and IFN-? production using murine bone marrow (BM)-derived Flt-3L induced dendritic cell culture. Microbial strains with such activity on pDC were absent in a diversity of bacillary strains, but were observed in certain spherical species (Lactococcus, Leuconostoc, Streptococcus and Pediococcus), which was correlated with their capacity for uptake by pDC. Detailed study of Lactococcus lactis subsp. lactis JCM5805 and JCM20101 revealed that the major type I and type III interferons were induced (IFN-?, -?, and ?). IFN-? induction was TLR9 and MyD88-dependent; a slight impairment was also observed in TLR4-/- cells. While these responses occurred with purified pDC, IFN-? production was synergistic upon co-culture with myeloid dendritic cells (mDC), an interaction that required direct mDC-pDC contact. L. lactis strains also stimulated expression of immunoregulatory receptors on pDC (ICOS-L and PD-L1), and accordingly augmented pDC induction of CD4+CD25+FoxP3+ Treg compared to the Lactobacillus strain. Oral administration of L. lactis JCM5805 induced significant activation of pDC resident in the intestinal draining mesenteric lymph nodes, but not in a remote lymphoid site (spleen). Taken together, certain non-pathogenic spherical LAB in wide dietary use has potent and diverse immunomodulatory effects on pDC potentially relevant to anti-viral immunity and chronic inflammatory disease. PMID:22505996

Jounai, Kenta; Ikado, Kumiko; Sugimura, Tetsu; Ano, Yasuhisa; Braun, Jonathan; Fujiwara, Daisuke

2012-01-01

128

A Novel Immunomodulatory Hemocyanin from the Limpet Fissurella latimarginata Promotes Potent Anti-Tumor Activity in Melanoma  

PubMed Central

Hemocyanins, the huge oxygen-transporting glycoproteins of some mollusks, are used as immunomodulatory proteins with proven anti-cancer properties. The biodiversity of hemocyanins has promoted interest in identifying new anti-cancer candidates with improved immunological properties. Hemocyanins promote Th1 responses without known side effects, which make them ideal for long-term sustained treatment of cancer. In this study, we evaluated a novel hemocyanin from the limpet/gastropod Fissurella latimarginata (FLH). This protein has the typical hollow, cylindrical structure of other known hemocyanins, such as the keyhole limpet hemocyanin (KLH) and the Concholepas hemocyanin (CCH). FLH, like the KLH isoforms, is composed of a single type of polypeptide with exposed N- and O-linked oligosaccharides. However, its immunogenicity was significantly greater than that of KLH and CCH, as FLH induced a stronger humoral immune response and had more potent anti-tumor activity, delaying tumor growth and increasing the survival of mice challenged with B16F10 melanoma cells, in prophylactic and therapeutic settings. Additionally, FLH-treated mice demonstrated increased IFN-? production and higher numbers of tumor-infiltrating CD4+ lymphocytes. Furthermore, in vitro assays demonstrated that FLH, but not CCH or KLH, stimulated the rapid production of pro-inflammatory cytokines (IL-6, IL-12, IL-23 and TNF-?) by dendritic cells, triggering a pro-inflammatory milieu that may explain its enhanced immunological activity. Moreover, this effect was abolished when deglycosylated FLH was used, suggesting that carbohydrates play a crucial role in the innate immune recognition of this protein. Altogether, our data demonstrate that FLH possesses increased anti-tumor activity in part because it activates a more potent innate immune response in comparison to other known hemocyanins. In conclusion, FLH is a potential new marine adjuvant for immunization and possible cancer immunotherapy. PMID:24466345

Arancibia, Sergio; Espinoza, Cecilia; Salazar, Fabian; Del Campo, Miguel; Tampe, Ricardo; Zhong, Ta-Ying; De Ioannes, Pablo; Moltedo, Bruno; Ferreira, Jorge; Lavelle, Ed C.; Manubens, Augusto; De Ioannes, Alfredo E.; Becker, Maria Ines

2014-01-01

129

Immunomodulatory sesquiterpene glycosides from Dendrobium nobile  

Microsoft Academic Search

Four sesquiterpene glycosides with alloaromadendrane, emmotin, and picrotoxane type aglycones were isolated from the stems of Dendrobium nobile Lindl (Orchidaceae). Their structures were determined by spectroscopic methods and chemical reactions. Immunomodulatory activity of the isolates was evaluated in vitro.

Qinghua Ye; Guowei Qin; Weimin Zhao

2002-01-01

130

Intravenous immunoglobulin promotes antitumor responses by modulating macrophage polarization.  

PubMed

Intravenous Igs (IVIg) therapy is widely used as an immunomodulatory strategy in inflammatory pathologies and is suggested to promote cancer regression. Because progression of tumors depends on their ability to redirect the polarization state of tumor-associated macrophages (from M1/immunogenic/proinflammatory to M2/anti-inflammatory), we have evaluated whether IVIg limits tumor progression and dissemination through modulation of macrophage polarization. In vitro, IVIg inhibited proinflammatory cytokine production from M1 macrophages and induced a M2-to-M1 polarization switch on human and murine M2 macrophages. In vivo, IVIg modified the polarization of tumor-associated myeloid cells in a Fc?r1? chain-dependent manner, modulated cytokine blood levels in tumor-bearing animals, and impaired tumor progression via Fc?RIII (CD16), Fc?RIV, and FcR? engagement, the latter two effects being macrophage mediated. Therefore, IVIg immunomodulatory activity is dependent on the polarization state of the responding macrophages, and its ability to trigger a M2-to-M1 macrophage polarization switch might be therapeutically useful in cancer, in which proinflammatory or immunogenic functions should be promoted. PMID:25326025

Domínguez-Soto, Angeles; de Las Casas-Engel, Mateo; Bragado, Rafael; Medina-Echeverz, José; Aragoneses-Fenoll, Laura; Martín-Gayo, Enrique; van Rooijen, Nico; Berraondo, Pedro; Toribio, María L; Moro, María A; Cuartero, Isabel; Castrillo, Antonio; Sancho, David; Sánchez-Torres, Carmen; Bruhns, Pierre; Sánchez-Ramón, Silvia; Corbí, Angel L

2014-11-15

131

Correlation between the synergistic effect of liposomes and endotoxins on the activation of macrophage tumoricidal activity and the effect of liposomes on the rough endoplasmic reticulum of macrophages  

Microsoft Academic Search

Summary Treatment of resident peritoneal macrophages of rats with small unilamellar vesicles of dipalmitoylphosphatidylcholine (DPPC SUV) potentiated their activation for tumor cell lysis by endotoxins. The fluorescence polarization of diphenylhexatriene (DPH) embedded in rough endoplasmic reticulum membranes isolated from DPPC SUV-treated macrophages was enhanced. The average fluorescence lifetime of DPH and the rotational correlation time deduced from anisotropy decay were

Jean François Jeannin; Roger Klein; Danièle Reisser; Patricia Lagadec; Michel Vincent; Irène Tatischeff

1988-01-01

132

Effect of low-level laser therapy on the modulation of the mitochondrial activity of macrophages  

PubMed Central

BACKGROUND: Macrophages play a major role among the inflammatory cells that invade muscle tissue following an injury. Low-level laser therapy (LLLT) has long been used in clinical practice to accelerate the muscle repair process. However, little is known regarding its effect on macrophages. OBJECTIVE: This study evaluated the effect of LLLT on the mitochondrial activity (MA) of macrophages. METHOD: J774 macrophages were treated with lipopolysaccharide (LPS) and interferon - gamma (IFN-?) (activation) for 24 h to simulate an inflammatory process, then irradiated with LLLT using two sets of parameters (780 nm; 70 mW; 3 J/cm2 and 660 nm; 15 mW; 7.5 J/cm2). Non-activated/non-irradiated cells composed the control group. MA was evaluated by the cell mitochondrial activity (MTT) assay (after 1, 3 and 5 days) in three independent experiments. The data were analyzed statistically. RESULTS: After 1 day of culture, activated and 780 nm irradiated macrophages showed lower MA than activated macrophages, but activated and 660 nm irradiated macrophages showed MA similar to activated cells. After 3 days, activated and irradiated (660 nm and 780 nm) macrophages showed greater MA than activated macrophages, and after 5 days, the activated and irradiated (660 nm and 780 nm) macrophages showed similar MA to the activated macrophages. CONCLUSIONS: These results show that 660 nm and 780 nm LLLT can modulate the cellular activation status of macrophages in inflammation, highlighting the importance of this resource and of the correct determination of its parameters in the repair process of skeletal muscle. PMID:25076002

Souza, Nadhia H. C.; Ferrari, Raquel A. M.; Silva, Daniela F. T.; Nunes, Fabio D.; Bussadori, Sandra K.; Fernandes, Kristianne P. S.

2014-01-01

133

LPS-inducible factor(s) from activated macrophages mediates cytolysis of Naegleria fowleri amoebae  

SciTech Connect

Soluble cytolytic factors of macrophage origin have previously been described with respect to their tumoricidal activity. The purpose of this study was to investigate the mechanism and possible factor(s) responsible for cytolysis of the amoeba Naegleria fowleri by activated peritoneal macrophages from B6C3F1 mice. Macrophages or conditioned medium (CM) from macrophage cultures were incubated with /sup 3/H-Uridine labeled amoebae. Percent specific release of label served as an index of cytolysis. Bacille Calmette-Guerin (BCG) and Corynebacterium parvum macrophages demonstrated significant cytolysis of amoebae at 24 h with an effector to target ratio of 10:1. Treatment of macrophages with inhibitors of RNA or protein synthesis blocked amoebicidal activity. Interposition of a 1 ..mu..m pore membrane between macrophages and amoebae inhibited killing. Inhibition in the presence of the membrane was overcome by stimulating the macrophages with LPS. CM from SPS-stimulated, but not unstimulated, cultures of activated macrophages was cytotoxic for amoebae. The activity was heat sensitive and was recovered from ammonium sulfate precipitation of the CM. Results indicate that amoebicidal activity is mediated by a protein(s) of macrophage origin induced by target cell contact or stimulation with LPS.

Cleary, S.F.; Marciano-Cabral, F.

1986-03-01

134

Review on medicinal uses, pharmacological, phytochemistry and immunomodulatory activity of plants.  

PubMed

Since ancient times, plants have been an exemplary source of medicine. Researchers have discovered some important compounds from plants. The present work constitutes a review of the medicinal plants whose immunomodulant activity has been proven. We performed PUBMED, EMBASE, Google scholar searches for research papers of medicinal plants having immunomodulant activity. Medicinal plants used by traditional physicians or reported as having immunomodulant activity include Acacia concocinna, Camellia sinensis, Lawsonia inermis Linn, Piper longum Linn, Gelidium amansii, Petroselinum crispum, Plantago major and Allium sativum. Immunomodulant activities of some of these medicinal plants have been investigated. The medicinal plants documented have immunomodulant activity and should be further investigated via clinical trial. PMID:25280022

Akram, M; Hamid, A; Khalil, A; Ghaffar, A; Tayyaba, N; Saeed, A; Ali, M; Naveed, A

2014-01-01

135

Oxidized LDL Induces Alternative Macrophage Phenotype through Activation of CD36 and PAFR  

PubMed Central

OxLDL is recognized by macrophage scavenger receptors, including CD36; we have recently found that Platelet-Activating Factor Receptor (PAFR) is also involved. Since PAFR in macrophages is associated with suppressor function, we examined the effect of oxLDL on macrophage phenotype. It was found that the presence of oxLDL during macrophage differentiation induced high mRNA levels to IL-10, mannose receptor, PPAR? and arginase-1 and low levels of IL-12 and iNOS. When human THP-1 macrophages were pre-treated with oxLDL then stimulated with LPS, the production of IL-10 and TGF-? significantly increased, whereas that of IL-6 and IL-8 decreased. In murine TG-elicited macrophages, this protocol significantly reduced NO, iNOS and COX2 expression. Thus, oxLDL induced macrophage differentiation and activation towards the alternatively activated M2-phenotype. In murine macrophages, oxLDL induced TGF-?, arginase-1 and IL-10 mRNA expression, which were significantly reduced by pre-treatment with PAFR antagonists (WEB and CV) or with antibodies to CD36. The mRNA expression of IL-12, RANTES and CXCL2 were not affected. We showed that this profile of macrophage activation is dependent on the engagement of both CD36 and PAFR. We conclude that oxLDL induces alternative macrophage activation by mechanisms involving CD36 and PAFR. PMID:24062612

Rios, Francisco J.; Koga, Marianna M.; Pecenin, Mateus; Gidlund, Magnus; Jancar, S.

2013-01-01

136

Conditioned medium from alternatively activated macrophages induce mesangial cell apoptosis via the effect of Fas  

SciTech Connect

During inflammation in the glomerulus, the proliferation of myofiroblast-like mesangial cells is commonly associated with the pathological process. Macrophages play an important role in regulating the growth of resident mesangial cells in the glomeruli. Alternatively activated macrophage (M2 macrophage) is a subset of macrophages induced by IL-13/IL-4, which is shown to play a repair role in glomerulonephritis. Prompted by studies of development, we performed bone marrow derived macrophage and rat mesangial cell co-culture study. Conditioned medium from IL-4 primed M2 macrophages induced rat mesangial cell apoptosis. The pro-apoptotic effect of M2 macrophages was demonstrated by condensed nuclei stained with Hoechst 33258, increased apoptosis rates by flow cytometry analysis and enhanced caspase-3 activation by western blot. Fas protein was up-regulated in rat mesangial cells, and its neutralizing antibody ZB4 partly inhibited M2 macrophage-induced apoptosis. The up-regulated arginase-1 expression in M2 macrophage also contributed to this apoptotic effect. These results indicated that the process of apoptosis triggered by conditioned medium from M2 macrophages, at least is partly conducted through Fas in rat mesangial cells. Our findings provide compelling evidence that M2 macrophages control the growth of mesangial cells in renal inflammatory conditions. - Highlights: • Conditioned-medium from M2 macrophages induces rat mesangial cell (MsC) apoptosis. • M2 macrophage conditioned medium exerts its pro-apoptotic effects via Fas ligand. • Arginase-1 activity in M2 macrophages plays a role in inducing apoptosis in rat MsC.

Huang, Yuan; Luo, Fangjun; Li, Hui; Jiang, Tao; Zhang, Nong, E-mail: nzhang@fudan.edu.cn

2013-11-15

137

Activation of peritoneal macrophages to cytoxicity against B16 melanoma cells by Serratia marcescens polyribosome fractions  

SciTech Connect

Serratia marcescens polyribosomes (SMPR) have been shown to elicit an anti-tumor response in vivo. The in-vitro effects of SMPR on macrophages as the nonspecific mediators of the anti-tumor response have not previously been examined. The first objective of this research project is to corroborate and analyze the in-vivo results by the development and application of an in-vitro cytotoxicity assay. The second objective is to examine the effect of SMPR upon previously unstimulated peritoneal macrophages as representing the mechanism of cytotoxicity. The third objective is to identify the minimal effective component of SMPR responsible for an effect on macrophages. Results revealed that SMPR preparations exert a number of effects upon macrophages. Morphologic changes included increased spreading and increased perinuclear vacuolization. Macrophages were shown to be metabolically activate by two lines of evidence. SMPR-treated macrophages exhibited increased cellular metabolism by the increased uptake of /sup 3/H-thymidine and by the increased levels of secreted leucine aminopeptidase as compared to control macrophages. Results also showed that SMPR activates macrophages to cytotoxicity against syngeneic tumor target cells. Buoyant-density fractions were isolated and assayed for macrophage activating ability. Results showed 50S ribosomal subunits to be the smallest fraction effective for macrophage activation. Both the RNA and protein were necessary for complete effectiveness.

Hoover, S.K.

1985-01-01

138

Transcriptome-Based Network Analysis Reveals a Spectrum Model of Human Macrophage Activation  

PubMed Central

Summary Macrophage activation is associated with profound transcriptional reprogramming. Although much progress has been made in the understanding of macrophage activation, polarization, and function, the transcriptional programs regulating these processes remain poorly characterized. We stimulated human macrophages with diverse activation signals, acquiring a data set of 299 macrophage transcriptomes. Analysis of this data set revealed a spectrum of macrophage activation states extending the current M1 versus M2-polarization model. Network analyses identified central transcriptional regulators associated with all macrophage activation complemented by regulators related to stimulus-specific programs. Applying these transcriptional programs to human alveolar macrophages from smokers and patients with chronic obstructive pulmonary disease (COPD) revealed an unexpected loss of inflammatory signatures in COPD patients. Finally, by integrating murine data from the ImmGen project we propose a refined, activation-independent core signature for human and murine macrophages. This resource serves as a framework for future research into regulation of macrophage activation in health and disease. PMID:24530056

Xue, Jia; Schmidt, Susanne V.; Sander, Jil; Draffehn, Astrid; Krebs, Wolfgang; Quester, Inga; De Nardo, Dominic; Gohel, Trupti D.; Emde, Martina; Schmidleithner, Lisa; Ganesan, Hariharasudan; Nino-Castro, Andrea; Mallmann, Michael R.; Labzin, Larisa; Theis, Heidi; Kraut, Michael; Beyer, Marc; Latz, Eicke; Freeman, Tom C.; Ulas, Thomas; Schultze, Joachim L.

2014-01-01

139

Characterization of the Conditioned Medium from Amniotic Membrane Cells: Prostaglandins as Key Effectors of Its Immunomodulatory Activity  

PubMed Central

We previously demonstrated that cells isolated from the mesenchymal region of the human amniotic membrane (human amniotic mesenchymal tissue cells, hAMTC) possess immunoregulatory roles, such as inhibition of lymphocyte proliferation and cytokine production, and suppression of generation and maturation of monocyte-derived dendritic cells, as reported for MSC from other sources. The precise factors and mechanisms responsible for the immunoregulatory roles of hAMTC remain unknown. In this study, we aimed to identify the soluble factors released by hAMTC and responsible for the anti-proliferative effect on lymphocytes, and the mechanisms underlying their actions, in vitro. Conditioned medium (CM) was prepared under routine culture conditions from hAMTC (CM-hAMTC) and also from fragments of the whole human amniotic membrane (CM-hAM). We analyzed the thermostability, chemical nature, and the molecular weight of the factors likely responsible for the anti-proliferative effects. We also evaluated the participation of cytokines known to be involved in the immunomodulatory actions of MSC from other sources, and attempted to block different synthetic pathways. We demonstrate that the inhibitory factors are temperature-stable, have a small molecular weight, and are likely of a non-proteinaceous nature. Only inhibition of cyclooxygenase pathway partially reverted the anti-proliferative effect, suggesting prostaglandins as key effector molecules. Factors previously documented to take part in the inhibitory effects of MSCs from other sources (HGF, TGF-?, NO and IDO) were not involved. Furthermore, we prove for the first time that the anti-proliferative effect is intrinsic to the amniotic membrane and cells derived thereof, since it is manifested in the absence of stimulating culture conditions, as opposed to MSC derived from the bone marrow, which possess an anti-proliferative ability only when cultured in the presence of activating stimuli. Finally, we show that the amniotic membrane could be an interesting source of soluble factors, without referring to extensive cell preparation. PMID:23071674

Rossi, Daniele; Pianta, Stefano; Magatti, Marta; Sedlmayr, Peter; Parolini, Ornella

2012-01-01

140

Phenotypic Diversity and Emerging New Tools to Study Macrophage Activation in Bacterial Infectious Diseases  

PubMed Central

Macrophage polarization is a concept that has been useful to describe the different features of macrophage activation related to specific functions. Macrophage polarization is responsible for a dichotomic approach (killing vs. repair) of the host response to bacteria; M1-type conditions are protective, whereas M2-type conditions are associated with bacterial persistence. The use of the polarization concept to classify the features of macrophage activation in infected patients using transcriptional and/or molecular data and to provide biomarkers for diagnosis and prognosis has most often been unsuccessful. The confrontation of polarization with different clinical situations in which monocytes/macrophages encounter bacteria obliged us to reappraise this concept. With the exception of M2-type infectious diseases, such as leprosy and Whipple’s disease, most acute (sepsis) or chronic (Q fever, tuberculosis) infectious diseases do not exhibit polarized monocytes/macrophages. This is also the case for commensals that shape the immune response and for probiotics that alter the immune response independent of macrophage polarization. We propose that the type of myeloid cells (monocytes vs. macrophages) and the kinetics of the immune response (early vs. late responses) are critical variables for understanding macrophage activation in human infectious diseases. Explorating the role of these new markers will provide important tools to better understand complex macrophage physiology.

Ka, Mignane B.; Daumas, Aurelie; Textoris, Julien; Mege, Jean-Louis

2014-01-01

141

The neuropathological and behavioral consequences of intraspinal microglial/macrophage activation.  

PubMed

Activated microglia and macrophages (CNS macrophages) have been implicated in the secondary or "bystander" pathology (e.g. axon injury, demyelination) that accompanies traumatic or autoimmune injury to the brain and spinal cord. These cells also can provide neurotrophic support and promote axonal regeneration. Studying the divergent functional potential of CNS macrophages in trauma models is especially difficult due to the various degradative mechanisms that are initiated prior to or concomitant with microglial/macrophage activation (e.g. hemorrhage, edema, excitotoxicity, lipid peroxidation). To study the potential impact of activated CNS macrophages on the spinal cord parenchyma, we have characterized an in vivo model of non-traumatic spinal cord neuroinflammation. Specifically, focal activation of CNS macrophages was achieved using stereotaxic microinjections of zymosan. Although microinjection does not cause direct mechanical trauma, localized activation of macrophages with zymosan acts as an "inflammatory scalpel" causing tissue injury at and nearby the injection site. The present data reveal that activation of CNS macrophages in vivo can result in permanent axonal injury and demyelination. Moreover, the pathology can be graded and localized to specific white matter tracts to produce quantifiable behavioral deficits. Further development of this model will help to clarify the biological potential of microglia and macrophages and the molecular signals that control their function within the spinal cord. PMID:12125741

Popovich, P G; Guan, Z; McGaughy, V; Fisher, L; Hickey, W F; Basso, D M

2002-07-01

142

Putting on the Brakes: Cyclic AMP as a Multipronged Controller of Macrophage Function  

NSDL National Science Digital Library

Macrophages orchestrate innate immune responses in tissues by activating various proinflammatory signaling programs. A key mechanism for preventing inflammatory disease states that result from excessive activation of such programs is the generation of the second messenger cyclic adenosine monophosphate (cAMP) by ligation of certain guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs). The pleiotropic actions of this cyclic nucleotide on various inflammatory functions of macrophages are mediated by diverse molecular mechanisms, including the assembly of distinct multiprotein complexes. A better understanding of crosstalk between cAMP signaling and proinflammatory pathways in macrophages may provide a basis for improved immunomodulatory strategies.

Marc Peters-Golden (Ann Arbor;University of Michigan Medical School REV)

2009-06-16

143

Host defence peptides: antimicrobial and immunomodulatory activity and potential applications for tackling antibiotic-resistant infections  

Microsoft Academic Search

The rapidly increasing incidence of multidrug-resistant infections and the alarmingly low rate of discovery of conventional antibiotics create an urgent need for alternative strategies to treat bacterial infections. Host defence peptides are short cationic molecules produced by the immune systems of most multicellular organisms; they are a class of compounds being actively researched. In this review, we provide an overview

A Nijnik; REW Hancock

2009-01-01

144

Immunomodulatory activity of alcoholic extract of Mangifera indica L. in mice  

Microsoft Academic Search

Mangifera indica Linn, a plant widely used in the traditional medicinal systems of India, has been reported to possess antiviral, antibacterial and anti-inflammatory activities. In the present study, the alcoholic extract of stem bark of Mangifera indica Linn (Extract I containing mangiferin 2.6%), has been investigated for its effect on cell mediated and humoral components of the immune system in

Neelam Makare; Subhash Bodhankar; Vinod Rangari

2001-01-01

145

The phosphoproteome of toll-like receptor-activated macrophages  

PubMed Central

Recognition of microbial danger signals by toll-like receptors (TLR) causes re-programming of macrophages. To investigate kinase cascades triggered by the TLR4 ligand lipopolysaccharide (LPS) on systems level, we performed a global, quantitative and kinetic analysis of the phosphoproteome of primary macrophages using stable isotope labelling with amino acids in cell culture, phosphopeptide enrichment and high-resolution mass spectrometry. In parallel, nascent RNA was profiled to link transcription factor (TF) phosphorylation to TLR4-induced transcriptional activation. We reproducibly identified 1850 phosphoproteins with 6956 phosphorylation sites, two thirds of which were not reported earlier. LPS caused major dynamic changes in the phosphoproteome (24% up-regulation and 9% down-regulation). Functional bioinformatic analyses confirmed canonical players of the TLR pathway and highlighted other signalling modules (e.g. mTOR, ATM/ATR kinases) and the cytoskeleton as hotspots of LPS-regulated phosphorylation. Finally, weaving together phosphoproteome and nascent transcriptome data by in silico promoter analysis, we implicated several phosphorylated TFs in primary LPS-controlled gene expression. PMID:20531401

Weintz, Gabriele; Olsen, Jesper V; Fruhauf, Katja; Niedzielska, Magdalena; Amit, Ido; Jantsch, Jonathan; Mages, Jorg; Frech, Cornelie; Dolken, Lars; Mann, Matthias; Lang, Roland

2010-01-01

146

Candidacidal mechanisms of peritoneal macrophages activated with lymphokines or gamma-interferon.  

PubMed

The mechanisms by which resident peritoneal macrophages, activated in vitro by lymphokines (LK) or recombinant gamma-interferon (IFN), kill Candida parapsilosis or C. albicans were studied. Resident non-activated peritoneal macrophages killed C. parapsilosis (55.5% SD 6.8%), but not C. albicans. This killing was completely inhibited by superoxide dismutase (SOD), partially by dimethyl sulphoxide (DMSO), but not by catalase or azide. Killing correlated with a brisk lucigenin-dependent chemiluminescence (CL) response by macrophages interacting with C. parapsilosis. No enhanced luminol-dependent CL response was observed in this system. This suggests that C. parapsilosis is killed by resident macrophages via a mechanism dependent on the presence of superoxide anion. By contrast, killing of C. parapsilosis by activated macrophages (49.0% SD 5.9%) was not inhibited by SOD or DMSO, suggesting the induction of a non-oxidative candidacidal mechanism. C. albicans was killed only by macrophages activated with IFN (52.0% SD 3.7%) or LK (55.7% SD 2.8%). Inhibition of killing by SOD was greater in IFN- than in LK-activated macrophages. Conversely, killing by LK-, but not IFN-, activated macrophages was significantly inhibited by catalase, DMSO or azide. The killing by LK-activated macrophages, and its inhibition by scavengers, correlated with the luminol-dependent CL response. The non-killing resident macrophages interacting with C. albicans made lucigenin-dependent CL responses similar to those of activated macrophages. The mechanisms enabling killing of C. albicans induced by activation appear to be different for LK and IFN, and appear to depend upon the myeloperoxidase systems and superoxide respectively. PMID:2494342

Brummer, E; Stevens, D A

1989-03-01

147

Immunomodulatory activity of alcoholic extract of Mangifera indica L. in mice.  

PubMed

Mangifera indica Linn, a plant widely used in the traditional medicinal systems of India, has been reported to possess antiviral, antibacterial and anti-inflammatory activities. In the present study, the alcoholic extract of stem bark of Mangifera indica Linn (Extract I containing mangiferin 2.6%), has been investigated for its effect on cell mediated and humoral components of the immune system in mice. Administration of test extract I produced increase in humoral antibody (HA) titre and delayed type hypersensitivity (DTH) in mice. It is concluded that test extract I is a promising drug with immunostimulant properties. PMID:11694357

Makare, N; Bodhankar, S; Rangari, V

2001-12-01

148

[Study of immunomodulatory activity of progesterone in an experimental model of Jurkat cells].  

PubMed

Progesterone plays important the role in the regulation of the immune system during pregnancy. We investigated the influence of progesterone on the activity of T-lymphocytes in a model system of Jurkat cells. Jurkat cells were stimulated with 50 ?g/ml of phytohemaglutinin A (PHA) at 370C for 5 minutes. Then, PHA was removed by centrifugation, the cells were washed and cultured for 24 hours alone or with progesterone (added to the incubation medium of Jurkat cells at a concentration of 0.07 and 0.7 ?l). The effect of progesterone on the level of apoptosis and expression of cytokines in jointly incubated intact and PHA-stimulated Jurkat cells. It was revealed that progesteron did not affect the intensity of apoptosis and cytokine expression in intact, but dose-dependently promotes intensification of apoptosis (to 88%) and inhibits the cytotoxic activity of jointly incubated intact and PHA-stimulated Jurkat cells (ratio of IL-2/IL-10 decreased from 2.56 to 1.53). PMID:25214285

2014-01-01

149

Liver X receptor activation stimulates iron export in human alternative macrophages  

PubMed Central

Rationale In atherosclerotic plaques, iron preferentially accumulates in macrophages where it can exert pro-oxidant activities. Objective The objective of this study is, first, to better characterize the iron distribution and metabolism in macrophage sub-populations in human atherosclerotic plaques and, second, to determine whether iron homeostasis is under the control of nuclear receptors, such as the Liver X Receptors (LXR). Methods and Results Here we report that iron depots accumulate in human atherosclerotic plaque areas enriched in CD68 and Mannose Receptor (MR) positive (CD68+MR+) alternative M2 macrophages. In vitro IL-4 polarization of human monocytes into M2 macrophages also resulted in a gene expression profile and phenotype favouring iron accumulation. However, upon iron exposure, M2 macrophages acquire a phenotype favouring iron release, through a strong increase in ferroportin expression, illustrated by a more avid oxidation of extra-cellular LDL by iron-loaded M2 macrophages. In line, in human atherosclerotic plaques, CD68+MR+ macrophages accumulate oxidized lipids, which activate Liver X Receptors (LXR? and LXR?), resulting in the induction of ABCA1, ABCG1 and ApoE expression. Moreover, in iron-loaded M2 macrophages, LXR activation induces nuclear factor erythroid 2-like 2 (NRF2) expression, hence increasing ferroportin expression, which, together with a decrease of hepcidin mRNA levels, promotes iron export. Conclusions These data identify a role for M2 macrophages in iron handling, a process which is regulated by LXR activation. PMID:24036496

Bories, Gael; Colin, Sophie; Vanhoutte, Jonathan; Derudas, Bruno; Copin, Corinne; Fanchon, Melanie; Daoudi, Mehdi; Belloy, Loic; Haulon, Stephan; Zawadzki, Christophe; Jude, Brigitte; Staels, Bart; Chinetti-Gbaguidi, Giulia

2013-01-01

150

Activation of Olfactory Receptors on Mouse Pulmonary Macrophages Promotes Monocyte Chemotactic Protein-1 Production  

PubMed Central

Background Emerging evidence suggests that non-olfactory tissues and cells can express olfactory receptors (ORs), however, the exact function of ectopic OR expression remains unknown. We have previously shown in mouse models that a unique cooperation between interferon-? (IFN-?) and lipopolysaccharide (LPS) drives the activation of pulmonary macrophages and leads to the induction of pathogenic responses in the respiratory tract. Further, through gene array studies, we have shown that activation of macrophages by these molecules results in the selective expression of a number of ORs. In this study, we validated the expression of these ORs in mouse airway and pulmonary macrophages in response to IFN-? and LPS (?/LPS) stimulation, and further explored the effect of odorant stimulation on macrophage function. Methodology/Principal Findings OR expression in airway and pulmonary macrophages in response to IFN-?, LPS or ?/LPS treatments was assessed by microarray and validated by q-PCR. OR expression (e.g. OR622) on macrophages was confirmed by visualization in immunofluoresence assays. Functional responses to odorants were assessed by quantifying inflammatory cytokine and chemokine expression using q-PCR and cell migration was assessed by a modified Boyden chamber migration assay. Our results demonstrate that eight ORs are expressed at basal levels in both airway and pulmonary macrophages, and that ?/LPS stimulation cooperatively increased this expression. Pulmonary macrophages exposed to the combined treatment of ?/LPS+octanal (an odorant) exhibited a 3-fold increase in MCP-1 protein production, compared to cells treated with ?/LPS alone. Supernatants from ?/LPS+octanal exposed macrophages also increased macrophage migration in vitro. Conclusions/Significance Eight different ORs are expressed at basal levels in pulmonary macrophages and expression is upregulated by the synergistic action of ?/LPS. Octanal stimulation further increased MCP-1 production and the motility of macrophages. Our results suggest that ORs may mediate macrophage function by regulating MCP-1 production and cell migration. PMID:24278251

Li, Jing Jing; Tay, Hock L.; Plank, Maximilian; Essilfie, Ama-Tawiah; Hansbro, Philip M.; Foster, Paul S.; Yang, Ming

2013-01-01

151

Palmitate- and lipopolysaccharide-activated macrophages evoke contrasting insulin responses in muscle cells.  

PubMed

Factors secreted by macrophages contribute to whole body insulin resistance, acting in part on adipose tissue. Muscle is the major tissue for glucose disposal, but how macrophage-derived factors impact skeletal muscle glucose uptake is unknown, or whether the macrophage environment influences this response. We hypothesized that conditioned medium from macrophages pretreated with palmitate or LPS would directly affect insulin action and glucose uptake in muscle cells. L6-GLUT4myc myoblasts were exposed to conditioned medium from RAW 264.7 macrophages pretreated with palmitate or LPS. Conditioned medium from palmitate-treated RAW 264.7 macrophages inhibited myoblast insulin-stimulated glucose uptake, GLUT4 translocation, and Akt phosphorylation while activating JNK p38 MAPK, decreasing IkappaBalpha, and elevating inflammation markers. Surprisingly, and opposite to its effects on adipose cells, conditioned medium from LPS-treated macrophages stimulated myoblast insulin-stimulated glucose uptake, GLUT4 translocation, and Akt phosphorylation without affecting stress kinases or inflammation indexes. This medium had markedly elevated IL-10 levels, and IL-10, alone, potentiated insulin action in myoblasts and partly reversed the insulin resistance imparted by medium from palmitate-treated macrophages. IL-10 neutralizing antibodies blunted the positive influence of LPS macrophage-conditioned medium. We conclude that myoblasts and adipocytes respond differently to cytokines. Furthermore, depending on their environment, macrophages negatively or positively influence muscle cells. Macrophages exposed to palmitate produce a mixture of proinflammatory cytokines that reduce insulin action in muscle cells; conversely, LPS-activated macrophages increase insulin action, likely via IL-10. Macrophages may be an integral element in glucose homeostasis in vivo, relaying effects of circulating factors to skeletal muscle. PMID:18840759

Samokhvalov, Victor; Bilan, Phillip J; Schertzer, Jonathan D; Antonescu, Costin N; Klip, Amira

2009-01-01

152

New tigliane-type diterpenoids from Euphorbia aellenii Rech. f. with immunomodulatory activity  

PubMed Central

The cytotoxic chloroform fraction of Euphorbia aellenii Rech. F. (Euphorbiaceae) afforded two new phorbol diterpenoids: 4-deoxy-4?-phorbol-12-(2,3-dimethyl) butyrate-13-isobutyrate and 17-hydroxy-4-deoxy-4?-phorbol-12-(2,3-dimethyl) butyrate-13-isobutyrate. Their structures were elucidated by NMR and other spectroscopic methods. The immunomodulating potentials of the isolated compounds were tested using standard proliferation and chemiluminescence assays. Compound 2 showed moderate inhibitory activity against both T-cell proliferation and reactive oxygen species (ROS) production in whole blood with IC50 of 14.0 ± 0.57 and 44.1 ± 3.8 ?g/ml, respectively, while compound 1 was relatively inactive with IC50 >50 ?g/mL for T-cell proliferation, and >100 ?g/mL for ROS. PMID:22049276

Ghanadian, M.; Ayatollahi, A.M.; Mesaik, M.A.; Afsharypuor, S.; Abdalla, O.M.; Kobarfard, F.

2011-01-01

153

Effect of gamma irradiation on mistletoe (Viscum album) lectin-mediated toxicity and immunomodulatory activity.  

PubMed

This study evaluated the effect of gamma irradiation on the reduction of the toxicity of mistletoe lectin using both in vitro and in vivo models. To extract the lectin from mistletoe, an (NH4)2SO4 precipitation method was employed and the precipitant purified using a Sepharose 4B column to obtain the pure lectin fraction. Purified lectin was then gamma-irradiated at doses of 0, 5, 10, 15, and 20 kGy, or heated at 100 °C for 30 min. Toxic effects of non-irradiated, irradiated, and heat-treated lectins were tested using hemagglutination assays, cytotoxicity assays, hepatotoxicity, and a mouse survival test and immunological response was tested using cytokine production activity. Hemagglutination of lectin was remarkably decreased (P < 0.05) by irradiation at doses exceeding 10 kGy and with heat treatment. However, lectin irradiated with 5 kGy maintained its hemagglutination activity. The cytotoxicity of lectin was decreased by irradiation at doses over 5 kGy and with heat treatment. In experiments using mouse model, glutamate oxaloacetate transaminase (GOT) and glutamic pyruvic transaminase (GPT) levels were decreased in the group treated with the 5 kGy irradiated and heat-treated lectins as compared to the intact lectin, and it was also shown that 5 kGy irradiated and heat-treated lectins did not cause damage in liver tissue or mortality. In the result of immunological response, tumor necrosis factor (TNF-?) and interleukin (IL-6) levels were significantly (P < 0.05) increased in the 5 kGy gamma-irradiated lectin treated group. These results indicate that 5 kGy irradiated lectin still maintained the immunological response with reduction of toxicity. Therefore, gamma-irradiation may be an effective method for reducing the toxicity of lectin maintaining the immune response. PMID:23847758

Sung, Nak-Yun; Byun, Eui-Baek; Song, Du-Sup; Jin, Yeung-Bae; Kim, Jae-Kyung; Park, Jong-Heum; Song, Beom-Seok; Jung, Pil-Mun; Byun, Myung-Woo; Lee, Ju-Woon; Park, Sang-Hyun; Kim, Jae-Hun

2013-01-01

154

Effect of gamma irradiation on mistletoe (Viscum album) lectin-mediated toxicity and immunomodulatory activity?  

PubMed Central

This study evaluated the effect of gamma irradiation on the reduction of the toxicity of mistletoe lectin using both in vitro and in vivo models. To extract the lectin from mistletoe, an (NH4)2SO4 precipitation method was employed and the precipitant purified using a Sepharose 4B column to obtain the pure lectin fraction. Purified lectin was then gamma-irradiated at doses of 0, 5, 10, 15, and 20 kGy, or heated at 100 °C for 30 min. Toxic effects of non-irradiated, irradiated, and heat-treated lectins were tested using hemagglutination assays, cytotoxicity assays, hepatotoxicity, and a mouse survival test and immunological response was tested using cytokine production activity. Hemagglutination of lectin was remarkably decreased (P < 0.05) by irradiation at doses exceeding 10 kGy and with heat treatment. However, lectin irradiated with 5 kGy maintained its hemagglutination activity. The cytotoxicity of lectin was decreased by irradiation at doses over 5 kGy and with heat treatment. In experiments using mouse model, glutamate oxaloacetate transaminase (GOT) and glutamic pyruvic transaminase (GPT) levels were decreased in the group treated with the 5 kGy irradiated and heat-treated lectins as compared to the intact lectin, and it was also shown that 5 kGy irradiated and heat-treated lectins did not cause damage in liver tissue or mortality. In the result of immunological response, tumor necrosis factor (TNF-?) and interleukin (IL-6) levels were significantly (P < 0.05) increased in the 5 kGy gamma-irradiated lectin treated group. These results indicate that 5 kGy irradiated lectin still maintained the immunological response with reduction of toxicity. Therefore, gamma-irradiation may be an effective method for reducing the toxicity of lectin maintaining the immune response. PMID:23847758

Sung, Nak-Yun; Byun, Eui-Baek; Song, Du-Sup; Jin, Yeung-Bae; Kim, Jae-Kyung; Park, Jong-Heum; Song, Beom-Seok; Jung, Pil-Mun; Byun, Myung-Woo; Lee, Ju-Woon; Park, Sang-Hyun; Kim, Jae-Hun

2013-01-01

155

Polymeric glycoconjugates protect and activate macrophages to promote killing of Bacillus cereus spores during phagocytosis  

Microsoft Academic Search

Diseases caused by Bacillus spores might be attenuated if macrophages were able to kill the spores on exposure. Glycoconjugate-bearing polymers, which\\u000a have been shown to bind to Bacillus spores, were tested for modulation of phagocytosis of B. cereus spores. Without glycoconjugate activation, murine macrophages were ineffective at killing Bacillus spores during phagocytosis. In the presence of glycoconjugates, however, the macrophages

Olga Tarasenko; Elizabeth Burton; Lee Soderberg; Pierre Alusta

2008-01-01

156

Activation-Induced Resistance of Human Macrophages to HIV1 Infection In Vitro1  

Microsoft Academic Search

Cells of the monocyte\\/macrophage lineage are the first targets of HIV-1 in patients and also serve as reservoirs for the virus during the course of infection. We investigated the effects of cell activation on early events of HIV-1 infection of monocyte-derived macrophages. Addition of LPS, a potent stimulator of macrophages, at the time of infection stimulated entry of HIV-1 into

Gabriele Zybarth; Norbert Reiling; Helena Schmidtmayerova; Barbara Sherry; Michael Bukrinsky

157

Molecular characteristics and immunomodulatory activities of water-soluble sulfated polysaccharides from Ulva pertusa.  

PubMed

Sulfated polysaccharides isolated from Ulva pertusa and fractionated using anion-exchange chromatography were investigated to determine their molecular characteristics and bioactivities. The crude and fractionated polysaccharides (F(1), F(2), and F(3)) were mainly composed of carbohydrates (59.9-65.9%), sulfates (11.6-15.3%), and uronic acid (7.30-16.4%) with small amounts of proteins (1.40-4.80%). Rhamnose (62.5-80.7%) was the major monosaccharide unit of these polysaccharides, with different levels of glucose (13.5-27.4%) and xylose (2.74-11.5%). The polysaccharides contained one or two major subfractions with weight-average molecular mass ranging from 51.1×10(3) to 1,690×10(3) g/mol. The relatively low in vitro anticancer activity of the polysaccharides (22.3-42.4%) suggested that they had little cytotoxicity against the cancer cell line used (AGS). On the other hand, the polysaccharides significantly stimulated Raw 264.7 cells, inducing considerable amounts of nitric oxide and various cytokines production, which suggested that they could be strong immunostimulators. PMID:22191629

Tabarsa, Mehdi; Han, Jung H; Kim, Chul Young; You, Sang Guan

2012-02-01

158

Antiviral, Immunomodulatory, and Free Radical Scavenging Activities of a Protein-Enriched Fraction from the Larvae of the Housefly, Musca domestica  

PubMed Central

In our previous study, protein-enriched fraction (PEF) that was isolated from the larvae of the housefly, Musca domestica L. (Diptera: Muscidae), showed excellent hepatoprotective activity as well as the potential for clinical application in therapy for liver diseases. In this study, antiviral, immunomodulatory, and free radical scavenging activities of PEF were evaluated. The antiviral results demonstrated that PEF inhibited the infection of avian influenza virus H9N2 and had a virucidal effect against the multicapsid nucleopolyhedrovirus of the alfalfa looper, Autographa californica Speyer (Lepidoptera: Noctuidae) in vitro. The mortality of silkworm larve in a PEF treatment group decreased significantly compared with a negative control. PEF showed excellent scavenging activity for 1,1-diphenyl-2-picrylhydrazyl and superoxide anion radicals, which were similar to those of ascorbic acid. The imunomodulatory results suggested that PEF could effectively improve immune function in experimental mice. Our results indicated that PEF could possibly be used for the prophylaxis and treatment of diseases caused by avian influenza virus infection. In addition, PEF with virucidal activity against insect viruses might provide useful for the development of antimicrobial breeding technology for economically important insects. As a natural product from insects, PEF could be a potential source for the discovery of potent antioxidant and immunomodulatory agents. PMID:24735244

Ai, Hui; Wang, Furong; Zhang, Na; Zhang, Lingyao; Lei, Chaoliang

2013-01-01

159

Activated Pulmonary Macrophages Are Insufficient for Resistance against Pneumocystis carinii  

PubMed Central

CD4+ T cells are pivotal for elimination of Pneumocystis carinii from infected lungs, and alveolar macrophages are considered the main effector cells clearing the infected host of P. carinii organisms. To investigate this issue, several mutant mouse strains were used in a previously established experimental setup which facilitates natural acquisition of disease through inhalation of airborne fungal organisms. Mutant mice deficient in major histocompatibility complex class II molecules (A??/?), T-cell receptor ?? cells (TCR??/?), or all mature T and B lymphocytes (RAG-1?/?) were naturally susceptible to P. carinii, whereas mouse mutants lacking the gamma interferon (IFN-?) receptor (IFN-?-R?/?) or tumor necrosis factor alpha (TNF-?) type I receptor (p55) (TNF-?-RI?/?) resisted disease acquisition. Analysis of pulmonary cytokine patterns and free radical expression revealed the presence of superoxide, nitric oxide, and interleukin-1 (IL-1) mRNA and elevated levels of IFN-?, TNF-?, and IL-12 in diseased TCR??/? and RAG-1?/? mice. Pulmonary macrophages of all diseased mouse mutants expressed scavenger and mannose receptors. Morbid A??/? mutants displayed significant NO levels and IL-1 mRNA only, whereas heterozygous controls did not exhibit any signs of disease. Interestingly, neither IFN-? nor TNF-? appeared to be essential for resisting natural infection with P. carinii, nor were these cytokines sufficient for mediating resistance during established disease in the absence of CD4+ T lymphocytes. Taken together, the results indicated that an activated phagocyte system, as evidenced by cytokine and NO secretion, in diseased mutants was apparently operative but did not suffice for parasite clearance in the absence of CD4+ TCR?? cells. Therefore, additional pathways, possibly involving interactions of inflammatory cytokines with CD4+ T lymphocytes, must contribute to successful resistance against P. carinii. PMID:9423872

Hanano, Ralph; Reifenberg, Kurt; Kaufmann, Stefan H. E.

1998-01-01

160

Regulation of IFN and TLR Signaling During Macrophage Activation by Opposing Feedforward and Feedback Inhibition Mechanisms  

PubMed Central

Summary Activated macrophages and their inflammatory products play a key role in innate immunity and in pathogenesis of autoimmune/inflammatory diseases. Macrophage activation needs to be tightly regulated to rapidly mount responses to infectious challenges but to avoid toxicity associated with excessive activation. Rapid and potent macrophage activation is driven by cytokine-mediated feedforward loops, while excessive activation is prevented by feedback inhibition. Here we discuss feedforward mechanisms that augment macrophage responses to Toll-like receptor (TLR) ligands and cytokines that are mediated by signal transducer and activator of transcription 1 (STAT1) and induced by interferon-? (IFN-?). IFN-? also drives full macrophage activation by inactivating feedback inhibitory mechanisms, such as those mediated by IL-10 and STAT3. Priming of macrophages with IFN-? reprograms cellular responses to other cytokines, such as type I IFNs and IL-10, with a shift toward pro-inflammatory STAT1-dominated responses. Similar but partially distinct priming effects are induced by other cytokines that activate STAT1, including type I IFNs and interleukin-27. We propose a model whereby opposing feedforward and feedback inhibition loops crossregulate each other to fine tune macrophage activation. In addition, we discuss how dysregulation of the balance between feedforward and feedback inhibitory mechanisms can contribute to the pathogenesis of autoimmune and inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus. PMID:19161415

Hu, Xiaoyu; Chakravarty, Soumya D.; Ivashkiv, Lionel B.

2008-01-01

161

Urokinase plasminogen activator receptor (CD87) expression of tumor-associated macrophages in ductal carcinoma in situ, breast cancer, and resident macrophages of normal breast tissue  

Microsoft Academic Search

Macrophages concentrate urokinase- type plasminogen activator (uPA) at the cell surface by expressing urokinase receptors (uPAR) in order to focus the pericellular space plasminogen-depen- dent proteolysis important in matrix remodeling and cell movement. This study examines the uPAR levels of tumor-associated macrophages (TAM) of invasive breast carcinomas, of TAMs from ductal carcinoma in situ (DCIS) and of macrophages derived from

Ralf Hildenbrand; Georg Wolf; Beatrix Bohme; Uwe Bleyl; Andrea Steinborn

162

Mechanistic study of macrophage activation by LPS stimulation using fluorescence imaging techinques  

NASA Astrophysics Data System (ADS)

Lipopolysaccharide (LPS), a structural component of the outer membrane of gram negative bacteria, has been suggested that stimulates macrophages secrete a wide variety of inflammatory mediators, such as nitric oxide (NO). However, the cellular mechanisms of NO generation in macrophage by LPS stimulation are not well known. In this study, LPS stimulated NO generation in macrophage was determined by measuring fluorescence changes with a NO specific probe DAF-FM DA. Using the fluorescence resonance energy transfer (FRET) techniques, we found an increase of protein kinase C (PKC) activation was dynamically monitored in macrophages treated with LPS. Nuclear factor kappa B (NF-?B) translocated from the cytoplasm to the nucleus in macrophage was measured by confocal laser scanning microscopy. Moreover, the PKC inhibitor GÖ6983 inhibited LPS-stimulated NF-?B activation and NO production. These results indicated that LPS stimulated NF-?B mediated NO production by activating PKC.

Lu, Cuixia; Zhou, Feifan; Chen, Wei R.; Xing, Da

2012-03-01

163

Mechanistic study of macrophage activation by LPS stimulation using fluorescence imaging techinques  

NASA Astrophysics Data System (ADS)

Lipopolysaccharide (LPS), a structural component of the outer membrane of gram negative bacteria, has been suggested that stimulates macrophages secrete a wide variety of inflammatory mediators, such as nitric oxide (NO). However, the cellular mechanisms of NO generation in macrophage by LPS stimulation are not well known. In this study, LPS stimulated NO generation in macrophage was determined by measuring fluorescence changes with a NO specific probe DAF-FM DA. Using the fluorescence resonance energy transfer (FRET) techniques, we found an increase of protein kinase C (PKC) activation was dynamically monitored in macrophages treated with LPS. Nuclear factor kappa B (NF-?B) translocated from the cytoplasm to the nucleus in macrophage was measured by confocal laser scanning microscopy. Moreover, the PKC inhibitor GÖ6983 inhibited LPS-stimulated NF-?B activation and NO production. These results indicated that LPS stimulated NF-?B mediated NO production by activating PKC.

Lu, Cuixia; Zhou, Feifan; Chen, Wei R.; Xing, Da

2011-11-01

164

Cooperation between Reactive Oxygen and Nitrogen Intermediates in Killing of Rhodococcus equi by Activated Macrophages  

Microsoft Academic Search

Rhodococcus equi is a facultative intracellular bacterium of macrophages which can infect immunocompro- mised humans and young horses. In the present study, we examine the mechanism of host defense against R. equi by using a murine model. We show that bacterial killing is dependent upon the presence of gamma interferon (IFN-g), which activates macrophages to produce reactive nitrogen and oxygen

PATRICIA A. DARRAH; MARY K. HONDALUS; QUIPING CHEN; HARRY ISCHIROPOULOS; DAVID M. MOSSER

2000-01-01

165

Molecular Interaction and Enzymatic Activity of Macrophage Migration Inhibitory Factor with Immunorelevant Peptides*  

E-print Network

Molecular Interaction and Enzymatic Activity of Macrophage Migration Inhibitory Factor T cell responses. Migration inhibitory factor (MIF) is a member of the thioredoxin family and has been in class II antigen presen- tation and/or as a chaperone is discussed. The macrophage migration inhibitory

Strominger, Jack L.

166

Studies on cytolytic mechanisms of activated macrophages and monocytes  

SciTech Connect

Pulmonary alveolar macrophages (PAM) and peripheral blood monocytes (PBMo) of the miniature swine can be converted to cytolytically active cells by treating with phorbol myristic acetate (PMA) or combined stimulation with recombinant human interferon - ..gamma.. (rHuIFN-..gamma..) and lipopolysaccharide (LPS). These activated PAM and PBMo become cytolytic to various targets by producing neutral proteases. H/sub 2/O/sub 2/ and cytotoxic factors. While the PAM stimulated by PMA was most active in generating H/sub 2/O/sub 2/ as well as neutral proteases, the PBMo stimulated with PMA was able to produce only H/sub 2/O/sub 2/. The mechanism of killing by PAM seemed to vary with type of target cells: H/sub 2/O/sub 2/ was effective in killing of PRBC, SRBC, and K562, but proteases were responsible for the lysis of U937 and WEHI-164. In contrast to PMA stimulation, combined stimulation with rHuIFN-..gamma.. and LPS was very effective in generation of cytotoxic factors from PAM and PBMo. These cytotoxic factors were directly toxic to various target cells including WEHI-164, U937, K562, and CRBC, but not to autologous target such as PRBC.

Chung, T.; Kim, Y.B.

1986-03-05

167

Macrophage expression of active MMP-9 induces acute plaque disruption in apoE-deficient mice  

PubMed Central

The majority of acute clinical manifestations of atherosclerosis are due to the physical rupture of advanced atherosclerotic plaques. It has been hypothesized that macrophages play a key role in inducing plaque rupture by secreting proteases that destroy the extracellular matrix that provides physical strength to the fibrous cap. Despite reports detailing the expression of multiple proteases by macrophages in rupture-prone regions, there is no direct proof that macrophage-mediated matrix degradation can induce plaque rupture. We aimed to test this hypothesis by retrovirally overexpressing the candidate enzyme MMP-9 in macrophages of advanced atherosclerotic lesions of apoE–/– mice. Despite a greater than 10-fold increase in the expression of MMP-9 by macrophages, there was only a minor increase in the incidence of plaque fissuring. Subsequent analysis revealed that macrophages secrete MMP-9 predominantly as a proform, and this form is unable to degrade the matrix component elastin. Expression of an autoactivating form of MMP-9 in macrophages in vitro greatly enhances elastin degradation and induces significant plaque disruption when overexpressed by macrophages in advanced atherosclerotic lesions of apoE–/– mice in vivo. These data show that enhanced macrophage proteolytic activity can induce acute plaque disruption and highlight MMP-9 as a potential therapeutic target for stabilizing rupture-prone plaques. PMID:16374516

Gough, Peter J.; Gomez, Ivan G.; Wille, Paul T.; Raines, Elaine W.

2006-01-01

168

Luteolin, a food-derived flavonoid, suppresses adipocyte-dependent activation of macrophages by inhibiting JNK activation.  

PubMed

Interaction between adipocytes and macrophages contributes to the development of insulin resistance in obese adipose tissues. In this study, we examined whether luteolin, food-derived flavonoid, could suppress the production of inflammatory mediators of the interaction between adipocytes and macrophages. Experiments using a coculture system of adipocytes and macrophages showed that luteolin suppressed the production of inflammatory mediators. In addition, activated macrophages were targets for the suppressive effect of luteolin. Luteolin inhibited the phosphorylation of JNK and suppressed the production of inflammatory mediators in the activated macrophages. The findings indicate that luteolin can inhibit the interaction between adipocytes and macrophages to suppress the production of inflammatory mediators, suggesting that luteolin is a valuable food-derived compound for the treatment of metabolic syndrome. PMID:19854181

Ando, Chieko; Takahashi, Nobuyuki; Hirai, Shizuka; Nishimura, Kanako; Lin, Shan; Uemura, Taku; Goto, Tsuyoshi; Yu, Rina; Nakagami, Joji; Murakami, Shigeru; Kawada, Teruo

2009-11-19

169

Antitumor and Immunomodulatory Effects of Polysaccharides from Broken-Spore of Ganoderma lucidum  

PubMed Central

The antitumor and immunomodulatory activity of broken-spore of Ganoderma lucidum polysaccharides (Gl-BSP) were investigated in vivo and in vitro. It was showed that Gl-BSP (50, 100, and 200?mg?kg?1) exhibited antitumor effect against Sarcoma 180 (S180) in BALB/c mice. The Gl-BSP was not cytotoxicity in S180 cells and PG cells (human lung carcinoma cell) in vitro. However, serum from Gl-BSP-treated S180-bearing mice significantly inhibited S180 and PG cells proliferation in vitro. Moreover, Gl-BSP promoted the splenic lymphocyte proliferation induced by Con A or LPS, enhanced nature killer cell (NK cell) cytotoxic activity, augmented the percentage of neutral red phagocytosis by macrophages, and increased the percentage of the CD4+ or CD8+ subset in S180-bearing mice. The serum level of IFN-?, TNF-?, and nitric oxide was increased by Gl-BSP. Gl-BSP also showed immunomodulatory activities in tumor-bearing mice. Furthermore, neutralization with anti-TNF-? and/or anti-IFN-? significantly diminished growth inhibition induced by Gl-BSP-treated serum of S180-bearing mice in S180 or PG cells. These observations suggest that the antitumor activity of Gl-BSP may be mainly related to the activation of the immune response of the host organism by the stimulation of NK cells, T cells, and macrophages. PMID:22811667

Wang, Peng-Yun; Zhu, Xiao-Ling; Lin, Zhi-Bin

2012-01-01

170

MicroRNAs Control Macrophage Formation and Activation: The Inflammatory Link between Obesity and Cardiovascular Diseases  

PubMed Central

Activation and recruitment of resident macrophages in tissues in response to physiological stress are crucial regulatory processes in promoting the development of obesity-associated metabolic disorders and cardiovascular diseases. Recent studies have provided compelling evidence that microRNAs play important roles in modulating monocyte formation, macrophage maturation, infiltration into tissues and activation. Macrophage-dependent systemic physiological and tissue-specific responses also involve cell-cell interactions between macrophages and host tissue niche cell components, including other tissue-resident immune cell lineages, adipocytes, vascular smooth muscle and others. In this review, we highlight the roles of microRNAs in regulating the development and function of macrophages in the context of obesity, which could provide insights into the pathogenesis of obesity-related metabolic syndrome and cardiovascular diseases. PMID:25014161

Chang, Richard Cheng-An; Ying, Wei; Bazer, Fuller W.; Zhou, Beiyan

2014-01-01

171

Pterins inhibit nitric oxide synthase activity in rat alveolar macrophages.  

PubMed Central

1. The synthesis of nitrite and citrulline from L-arginine by immune-stimulated rat alveolar macrophages and the modulation of this synthesis were studied. 2,4-Diamino-6-hydroxypyrimidine (DAHP), 6R-5,6,7,8-tetrahydro-L-biopterin (BH4) and L-sepiapterin were potent inhibitors of the recombinant interferon-gamma induced production of nitrogen oxides in intact cultured cells with I50 values for BH4 and L-sepiapterin of approximately 10 microM. They were equally effective in inhibiting the induced production of citrulline. This inhibitory effect was concentration-dependent for all three modulators investigated. 2. The inhibitory effects were not dependent on incubation times of either 24 or 48 h, on the immune-stimulus used (lipopolysaccharide, interferon-gamma), or whether these stimuli were added during or after the induction period. 3. Pterin-6-carboxylic acid (PCA), which cannot be converted into BH4, and methotrexate (MTX), which inhibits dihydrofolatereductase but not de novo biosynthesis of BH4, did not change the production of nitrite. 4. The data indicate that DAHP, an inhibitor of the de novo biosynthesis of the co-factor BH4, blocks the nitric oxide synthase activity in intact cells. Since the pterins BH4 and L-sepiapterin blocked the L-arginine dependent production of nitrite and citrulline, the activity of nitric oxide synthase in phagocytic cells may be regulated by metabolic endproducts of the de novo biosynthesis of BH4. PMID:1281717

Jorens, P. G.; van Overveld, F. J.; Bult, H.; Vermeire, P. A.; Herman, A. G.

1992-01-01

172

Dysfunctional CFTR Alters the Bactericidal Activity of Human Macrophages against Pseudomonas aeruginosa  

PubMed Central

Chronic inflammation of the lung, as a consequence of persistent bacterial infections by several opportunistic pathogens represents the main cause of mortality and morbidity in cystic fibrosis (CF) patients. Mechanisms leading to increased susceptibility to bacterial infections in CF are not completely known, although the involvement of cystic fibrosis transmembrane conductance regulator (CFTR) in microbicidal functions of macrophages is emerging. Tissue macrophages differentiate in situ from infiltrating monocytes, additionally, mature macrophages from different tissues, although having a number of common activities, exhibit variation in some molecular and cellular functions. In order to highlight possible intrinsic macrophage defects due to CFTR dysfunction, we have focused our attention on in vitro differentiated macrophages from human peripheral blood monocytes. Here we report on the contribution of CFTR in the bactericidal activity against Pseudomonas aeruginosa of monocyte derived human macrophages. At first, by real time PCR, immunofluorescence and patch clamp recordings we demonstrated that CFTR is expressed and is mainly localized to surface plasma membranes of human monocyte derived macrophages (MDM) where it acts as a cAMP-dependent chloride channel. Next, we evaluated the bactericidal activity of P. aeruginosa infected macrophages from healthy donors and CF patients by antibiotic protection assays. Our results demonstrate that control and CF macrophages do not differ in the phagocytic activity when infected with P. aeruginosa. Rather, although a reduction of intracellular live bacteria was detected in both non-CF and CF cells, the percentage of surviving bacteria was significantly higher in CF cells. These findings further support the role of CFTR in the fundamental functions of innate immune cells including eradication of bacterial infections by macrophages. PMID:21625641

Porto, Paola Del; Cifani, Noemi; Guarnieri, Simone; Di Domenico, Enea Gino; Mariggio, Maria A.; Spadaro, Francesca; Guglietta, Silvia; Anile, Marco; Venuta, Federico; Quattrucci, Serena; Ascenzioni, Fiorentina

2011-01-01

173

Classical versus alternative macrophage activation: the Ying and the Yang in host defense against pulmonary fungal infections.  

PubMed

Macrophages are innate immune cells that possess unique abilities to polarize toward different phenotypes. Classically activated macrophages are known to have major roles in host defense against various microbial pathogens, including fungi, while alternatively activated macrophages are instrumental in immune-regulation and wound healing. Macrophages in the lungs are often the first responders to pulmonary fungal pathogens, and the macrophage polarization state has the potential to be a deciding factor in disease progression or resolution. This review discusses the distinct macrophage polarization states and their roles during pulmonary fungal infection. We focus primarily on Cryptococcus neoformans and Pneumocystis model systems as disease resolution of these two opportunistic fungal pathogens is linked to classically or alternatively activated macrophages, respectively. Further research considering macrophage polarization states that result in anti-fungal activity has the potential to provide a novel approach for the treatment of fungal infections. PMID:25073676

Leopold Wager, C M; Wormley, F L

2014-09-01

174

Macrophage activation by factors released from acetaminophen-injured hepatocytes. Potential role of HMGB1  

PubMed Central

Toxic doses of acetaminophen (AA) cause hepatocellular necrosis. Evidence suggests that activated macrophages contribute to the pathogenic process; however, the factors that activate these cells are unknown. In these studies, we assessed the role of mediators released from AA-injured hepatocytes in macrophage activation. Treatment of macrophages with conditioned medium (CM) collected 24 hr after treatment of mouse hepatocytes with 5 mM AA (CM-AA) resulted in increased production of reactive oxygen species (ROS). Macrophage expression of heme oxygenase-1 (HO-1) and catalase mRNA was also upregulated by CM-AA, as well as cyclooxygenase (COX)-2 and 12/15-lipoxygenase (LOX). CM-AA also upregulated expression of the proinflammatory chemokines, MIP-1? and MIP-2. The effects of CM-AA on expression of COX-2, MIP-1? and MIP-2 were inhibited by blockade of p44/42 MAP kinase, suggesting a biochemical mechanism mediating macrophage activation. Hepatocytes injured by AA were found to release HMGB1, a potent macrophage activator. This was inhibited by pretreatment of hepatocytes with ethyl pyruvate (EP), which blocks HMGB1 release. EP also blocked CM-AA induced ROS production and antioxidant expression, and reduced expression of COX-2, but not MIP-1? or MIP-2. These findings suggest that HMGB1 released by AA-injured hepatocytes contributes to macrophage activation. This is supported by our observation that expression of the HMGB1 receptor RAGE is upregulated in macrophages in response to CM-AA. These data indicate that AA-injured hepatocytes contribute to the inflammatory environment in the liver through the release of mediators such as HMGB1. Blocking HMGB1/RAGE may be a useful approach to limiting classical macrophage activation and AA-induced hepatotoxicity. PMID:21513726

Dragomir, Ana-Cristina; Laskin, Jeffrey D.; Laskin, Debra L.

2012-01-01

175

Macrophage Activation in Atherosclerosis: Pathogenesis and Pharmacology of Plaque Rupture  

Microsoft Academic Search

Atherosclerosis is still an important disease. It accounts for 39% of deaths in the U.K. and 12 million U.S citizens have atherosclerosis-associated disease. Atherosclerosis may exert clinical effects by slow narrowing, producing stable angina or dramatic rupture, producing acute coronary syndromes such as unstable angina or myocardial infarction and death. Macrophages are abundant in ruptured atherosclerotic plaques. Macrophages are innate

J. J. Boyle

2005-01-01

176

Immunomodulatory Activity and Protective Effects of Polysaccharide from Eupatorium adenophorum Leaf Extract on Highly Pathogenic H5N1 Influenza Infection  

PubMed Central

The development of novel broad-spectrum, antiviral agents against H5N1 infection is urgently needed. In this study, we evaluated the immunomodulatory activities and protective effect of Eupatorium adenophorum polysaccharide (EAP) against the highly pathogenic H5N1 subtype influenza virus. EAP treatment significantly increased the production of IL-6, TNF-?, and IFN-? both in vivo and in vitro as measured by qPCR and ELISA. In a mouse infection model, intranasal administration of EAP at a dose of 25?mg/kg body weight prior to H5N1 viral challenge efficiently inhibited viral replication, decreased lung lesions, and increased survival rate. We further evaluated the innate immune recognition of EAP, as this process is regulated primarily Dectin-1 and mannose receptor (MR). These results indicate that EAP may have immunomodulatory properties and a potential prophylactic effect against H5N1 influenza infection. Our investigation suggests an alternative strategy for the development of novel antiinfluenza agents and benefits of E. adenophorum products. PMID:24159339

Hou, Lingyu

2013-01-01

177

Immunomodulatory and therapeutic potential of a mycelial lectin from Aspergillus nidulans.  

PubMed

Lectins bind to surface receptors on target cells, and activate a cascade of events, eventually leading to altered immune status of host. The immunomodulatory potential of purified lectin from Aspergillus nidulans was evaluated in Swiss albino mice treated intraperitoneally with seven different doses of purified lectin. Lectin prevented BSA-induced Arthus reaction and systemic anaphylaxis. The enhanced functional ability of macrophages was evident from respiratory burst activity and nitric oxide production in splenocyte cultures. Interferon-gamma and interleukin-6 levels were significantly up-regulated in treated groups. Maximum stimulatory effect was observed at the dose of 1.5 mg/kg body weight. Therapeutic potential of A. nidulans lectin was assessed against trinitrobenzene sulfonic acid-induced ulcerative colitis in male Wistar rats. Rats pre-treated with 80 mg/kg body weight of purified lectin intraperitoneally prior to colitis induction showed lesser disease severity and recovery within 7 days, while rats post-treated with the same dose showed recovery in 11 days. The results demonstrate immunomodulatory effects of A. nidulans lectin in Swiss albino mice, resulting in improved immune status of the animals and unfold its curative effect against ulcerative colitis in rat model. This is the first report on immunomodulatory and therapeutic potential of a lectin from microfungi. PMID:21590306

Singh, Ram Sarup; Bhari, Ranjeeta; Rana, Vikas; Tiwary, Ashok Kumar

2011-09-01

178

Mucosal immunoadjuvant activity of liposomes: role of alveolar macrophages.  

PubMed Central

Previously, we have reported on a liposomal adjuvant system for stimulation of both systemic IgG and mucosal s-IgA responses against viral antigens (influenza virus subunit antigen or whole inactivated measles virus) administered intranasally to mice. Immune stimulation is observed with negatively charged, but not with zwitterionic, liposomes and is independent of a physical association of the antigen with the liposomes. Furthermore, liposome-mediated immune stimulation requires deposition of the liposomes and the antigen in the lower respiratory tract. In the present study, it is shown that alveolar macrophages (AM) are the main target cells for negatively charged liposomes administered to the lungs of mice. AM isolated from animals, to which negatively charged liposomes were administered beforehand, showed large intracellular vacuoles, suggestive of massive liposome uptake. Under ex vivo conditions, both AM and RAW 264 cells exhibited a high capacity to take up negatively charged liposomes. The deposition of negatively charged liposomes, but not zwitterionic, liposomes in the lung reduced the phagocytic and migratory behaviour of AM, as assessed on the basis of transport of carbon particles to the draining lymph nodes of the lungs. Depletion of AM in vivo with dichloromethylene diphosphonate, facilitated an enhanced systemic and local antibody response against influenza subunit antigen deposited subsequently to the lower respiratory tract. In conclusion, these data provide support for the hypothesis that uptake of negatively charged liposomes blocks the immunosuppressive activity of AM, thereby facilitating local and systemic antibody responses. Images Figure 1 PMID:9014811

de Haan, A; Groen, G; Prop, J; van Rooijen, N; Wilschut, J

1996-01-01

179

In vitro antiviral and immunomodulatory activity of arbidol and structurally related derivatives in herpes simplex virus type 1-infected human keratinocytes (HaCat).  

PubMed

Arbidol (ARB) is an antiviral drug that has broad-spectrum activity against a number of viral infections. To date, there are no specific data regarding its effects against a herpesvirus. Here, the in vitro antiviral effect of ARB and structurally related derivatives were evaluated in HaCat cells on different steps of herpes simplex virus type 1 replication: adsorption, entry and post-entry. The simplified pyrrolidine analogue, 9a2, showed the best antiviral activity in vitro by reducing the plaque numbers by about 50?% instead of 42?% obtained with ARB at the same concentration. Furthermore, we have reported that all tested compounds evaluated for their immunomodulatory activity showed the ability to reduce the viral proteins VP16 and ICP27 and to modify the virus-induced cytokine expression, allowing the host cell a more efficient antiviral response. PMID:25187601

Perfetto, Brunella; Filosa, Rosanna; De Gregorio, Vincenza; Peduto, Antonella; La Gatta, Annalisa; de Caprariis, Paolo; Tufano, Maria Antonietta; Donnarumma, Giovanna

2014-11-01

180

Regulation of Macrophage Function by Adenosine  

PubMed Central

Following its release into the extracellular space in response to metabolic disturbances, the endogenous nucleoside adenosine exerts a range of immunomodulatory effects and cells of the mononuclear phagocyte system are among its major targets. Adenosine governs mononuclear phagocyte functions via 4 G-protein–coupled cell membrane receptors, which are denoted A1, A2A, A2B, and A3 receptors. Adenosine promotes osteoclast differentiation via A1 receptors and alters monocyte to dendritic cell differentiation through A2B receptors. Adenosine downregulates classical macrophage activation mainly through A2A receptors. In contrast A2B receptor activation upregulates alternative macrophage activation. Adenosine promotes angiogenesis, which is mediated by inducing the production of vascular endothelial growth factor by mononuclear phagocytes through A2A, A2B, and A3 receptors. By regulating mononuclear phagocyte function adenosine dictates the course of inflammatory and vascular diseases and cancer. PMID:22423038

Hasko, Gyorgy; Pacher, Pal

2012-01-01

181

Cot/tpl2 participates in the activation of macrophages by adiponectin.  

PubMed

Whereas the main function of APN is to enhance insulin activity, it is also involved in modulating the macrophage phenotype. Here, we demonstrate that at physiological concentrations, APN activates Erk1/2 via the IKK?-p105/NF-??1-Cot/tpl2 intracellular signal transduction cassette in macrophages. In peritoneal macrophages stimulated with APN, Cot/tpl2 influences the ability to phagocytose beads. However, Cot/tpl2 did not modulate the known capacity of APN to decrease lipid content in peritoneal macrophages in response to treatment with oxLDL or acLDL. A microarray analysis of gene-expression profiles in BMDMs exposed to APN revealed that APN modulated the expression of ?3300 genes; the most significantly affected biological functions were the inflammatory and the infectious disease responses. qRT-PCR analysis of WT and Cot/tpl2 KO macrophages stimulated with APN for 0, 3, and 18 h revealed that Cot/tpl2 participated in the up-regulation of APN target inflammatory mediators included in the cytokine-cytokine receptor interaction pathway (KEGG ID 4060). In accordance with these data, macrophages stimulated with APN increased secretion of cytokines and chemokines, including IL-1?, IL-1?, TNF-?, IL-10, IL-12, IL-6, and CCL2. Moreover, Cot/tpl2 also played an important role in the production of these inflammatory mediators upon stimulation of macrophages with APN. It has been reported that different types of signals that stimulate TLRs, IL-1R, TNFR, Fc?R, and proteinase-activated receptor-1 activate Cot/tpl2. Here, we demonstrate that APN is a new signal that activates the IKK?-p105/NF-??1-Cot/tpl2-MKK1/2-Erk1/2 axis in macrophages. Furthermore, this signaling cassette modulates the biological functions triggered by APN in macrophages. PMID:24532642

Sanz-Garcia, Carlos; Nagy, Laura E; Lasunción, Miguel A; Fernandez, Margarita; Alemany, Susana

2014-06-01

182

Nonpathogenic Lactobacillus rhamnosus activates the inflammasome and antiviral responses in human macrophages  

PubMed Central

In this study, we have utilized global gene expression profiling to compare the responses of human primary macrophages to two closely related, well-characterized Lactobacillus rhamnosus strains GG and LC705, since our understanding of the responses elicited by nonpathogenic bacteria in human innate immune system is limited. Macrophages are phagocytic cells of the innate immune system that perform sentinel functions to initiate appropriate responses to surrounding stimuli. Macrophages that reside on gut mucosa encounter ingested and intestinal bacteria. Bacteria of Lactobacillus genus are nonpathogenic and used in food and as supplements with health-promoting probiotic potential. Our results demonstrate that live GG and LC705 induced quantitatively different gene expression profiles in macrophages. A gene ontology analysis revealed functional similarities and differences in responses to GG and LC705 that were reflected in host defense responses. Both GG and LC705 induced interleukin-1? production in macrophages that required caspase-1 activity. LC705, but not GG, induced type I interferon -dependent gene activation that correlated with its ability to prevent influenza A virus replication and production of viral proteins in macrophages. Our results indicate that nonpathogenic bacteria are able to activate the inflammasome. In addition, our results suggest that L. rhamnosus may prime the antiviral potential of human macrophages. PMID:22895087

Miettinen, Minja; Pietila, Taija E.; Kekkonen, Riina A.; Kankainen, Matti; Latvala, Sinikka; Pirhonen, Jaana; Osterlund, Pamela; Korpela, Riitta; Julkunen, Ilkka

2012-01-01

183

Transcellular regulation of cell respiration by nitric oxide generated by activated macrophages  

Microsoft Academic Search

A macrophage cell line (J774), activated with interferon-? and endotoxin to express the inducible form of NO synthase (iNOS), immediately inhibited the cellular respiration of co-incubated L-929 fibroblasts or non-activated J774 macrophages. The inhibition was potent, rapid and reversible when the NO was removed by adding oxyhaemoglobin or by inhibiting iNOS. Exogenously added NO also rapidly and reversibly inhibited cellular

Guy C Brown; Neale Foxwell; Salvador Moncada

1998-01-01

184

Immunomodulatory Activity of Dietary Fiber: Arabinoxylan and Mixed-Linked Beta-Glucan Isolated from Barley Show Modest Activities in Vitro  

PubMed Central

High intake of dietary fiber is claimed to protect against development of colorectal cancer. Barley is a rich source of dietary fiber, and possible immunomodulatory effects of barley polysaccharides might explain a potential protective effect. Dietary fiber was isolated by extraction and enzyme treatment. A mixed-linked ?-glucan (WSM-TPX, 96.5% ?-glucan, Mw 886 kDa), an arabinoxylan (WUM-BS-LA, 96.4% arabinoxylan, Mw 156 kDa), a mixed-linked ?-glucan rich fraction containing 10% arabinoxylan (WSM-TP) and an arabinoxylan rich fraction containing 30% mixed-linked ?-glucan (WUM-BS) showed no significant effect on IL-8 secretion and proliferation of two intestinal epithelial cell lines, Caco-2 and HT-29, and had no significant effect on the NF-?B activity in the monocytic cell line U937-3?B-LUC. Further enriched arabinoxylan fractions (WUM-BS-LA) from different barley varieties (Tyra, NK96300, SB94897 and CDCGainer) were less active than the mixed-linked ?-glucan rich fractions (WSM-TP and WSM-TPX) in the complement-fixing test. The mixed-linked ?-glucan rich fraction from NK96300 and CDCGainer showed similar activities as the positive control while mixed-linked ?-glucan rich fractions from Tyra and SB94897 were less active. From these results it is concluded that the isolated high molecular weight mixed-linked ?-glucans and arabinoxylans from barley show low immunological responses in selected in vitro test systems and thus possible anti-colon cancer effects of barley dietary fiber cannot be explained by our observations. PMID:21340001

Samuelsen, Anne Berit; Rieder, Anne; Grimmer, Stine; Michaelsen, Terje E.; Knutsen, Svein H.

2011-01-01

185

Metabolic Characterization of Leishmania major Infection in Activated and Nonactivated Macrophages.  

PubMed Central

Infection with Leishmania spp. can lead to a range of symptoms in the affected individual, depending on underlying immune-metabolic processes. The macrophage activation state hereby plays a key role. Whereas the l-arginine pathway has been described in detail as the main biochemical process responsible for either nitric oxide mediated parasite killing (classical activation) or amplification of parasite replication (alternative activation), we were interested in a wider characterization of metabolic events in vitro. We therefore assessed cell growth medium, parasite extract, and intra- and extracellular metabolome of activated and nonactivated macrophages, in presence and absence of Leishmania major. A metabolic profiling approach was applied combining 1H NMR spectroscopy with multi- and univariate data treatment. Metabolic changes were observed along both conditional axes, that is, infection state and macrophage activation, whereby significantly higher levels of potential parasite end products were found in parasite exposed samples including succinate, acetate, and alanine, compared to uninfected macrophages. The different macrophage activation states were mainly discriminated by varying glucose consumption. The presented profiling approach allowed us to obtain a metabolic snapshot of the individual biological compartments in the assessed macrophage culture experiments and represents a valuable read out system for further multiple compartment in vitro studies. PMID:22724526

2012-01-01

186

EXTRACELLULAR CYTOLYSIS BY ACTIVATED MACROPHAGES AND GRANULOCYTES I. Pharmacologic Triggering of Effector Cells and the Release of Hydrogen Peroxide  

Microsoft Academic Search

Until recently, we knew of no biochemical basis for the cytotoxic activity of any mononuclear leukocyte (macrophage or lymphocyte). Thymidine (1) and arginase (2, 3) are now thought to account for some of the in vitro cytostatic and cytolytic effects of macrophages. However, those molecules seem unlikely to mediate similar effects of macrophages in vivo, except perhaps in areas of

CARL F. NATHAN; LINDA H. BRUKNER; SAMUEL C. SILVERSTEIN; ZANVIL A. COHN

187

Chitosan-induced phospholipase A2 activation and arachidonic acid mobilization in P388D1 macrophages  

E-print Network

). Collectively, the results of this work establish chitosan as a novel macrophage- activating factor that elicits and macrophages [4]. Histological ¢ndings suggest that these com- pounds stimulate the migration factor, interleu- kin-1 and colony-stimulating factor by macrophages and to induce immunologic adjuvant e

Dennis, Edward A.

188

Chitohexaose Activates Macrophages by Alternate Pathway through TLR4 and Blocks Endotoxemia  

PubMed Central

Sepsis is a consequence of systemic bacterial infections leading to hyper activation of immune cells by bacterial products resulting in enhanced release of mediators of inflammation. Endotoxin (LPS) is a major component of the outer membrane of Gram negative bacteria and a critical factor in pathogenesis of sepsis. Development of antagonists that inhibit the storm of inflammatory molecules by blocking Toll like receptors (TLR) has been the main stay of research efforts. We report here that a filarial glycoprotein binds to murine macrophages and human monocytes through TLR4 and activates them through alternate pathway and in the process inhibits LPS mediated classical activation which leads to inflammation associated with endotoxemia. The active component of the nematode glycoprotein mediating alternate activation of macrophages was found to be a carbohydrate residue, Chitohexaose. Murine macrophages and human monocytes up regulated Arginase-1 and released high levels of IL-10 when incubated with chitohexaose. Macrophages of C3H/HeJ mice (non-responsive to LPS) failed to get activated by chitohexaose suggesting that a functional TLR4 is critical for alternate activation of macrophages also. Chitohexaose inhibited LPS induced production of inflammatory molecules TNF-?, IL-1? and IL-6 by macropahges in vitro and in vivo in mice. Intraperitoneal injection of chitohexaose completely protected mice against endotoxemia when challenged with a lethal dose of LPS. Furthermore, Chitohexaose was found to reverse LPS induced endotoxemia in mice even 6/24/48 hrs after its onset. Monocytes of subjects with active filarial infection displayed characteristic alternate activation markers and were refractory to LPS mediated inflammatory activation suggesting an interesting possibility of subjects with filarial infections being less prone to develop of endotoxemia. These observations that innate activation of alternate pathway of macrophages by chtx through TLR4 has offered novel opportunities to cell biologists to study two mutually exclusive activation pathways of macrophages being mediated through a single receptor. PMID:22654663

Panda, Santosh K.; Kumar, Sunil; Tupperwar, Nitin C.; Vaidya, Tushar; George, Anna; Rath, Satyajit; Bal, Vineeta; Ravindran, Balachandran

2012-01-01

189

Relationship of MMP-14 and TIMP-3 Expression with Macrophage Activation and Human Atherosclerotic Plaque Vulnerability  

PubMed Central

Matrix metalloproteinase-14 (MMP-14) promotes vulnerable plaque morphology in mice, whereas tissue inhibitor of metalloproteinases-3 (TIMP-3) overexpression is protective. MMP-14hi??TIMP-3lo rabbit foam cells are more invasive and more prone to apoptosis than MMP-14lo??TIMP-3hi cells. We investigated the implications of these findings for human atherosclerosis. In vitro generated macrophages and foam-cell macrophages, together with atherosclerotic plaques characterised as unstable or stable, were examined for expression of MMP-14, TIMP-3, and inflammatory markers. Proinflammatory stimuli increased MMP-14 and decreased TIMP-3 mRNA and protein expression in human macrophages. However, conversion to foam-cells with oxidized LDL increased MMP-14 and decreased TIMP-3 protein, independently of inflammatory mediators and partly through posttranscriptional mechanisms. Within atherosclerotic plaques, MMP-14 was prominent in foam-cells with either pro- or anti-inflammatory macrophage markers, whereas TIMP-3 was present in less foamy macrophages and colocalised with CD206. MMP-14 positive macrophages were more abundant whereas TIMP-3 positive macrophages were less abundant in plaques histologically designated as rupture prone. We conclude that foam-cells characterised by high MMP-14 and low TIMP-3 expression are prevalent in rupture-prone atherosclerotic plaques, independent of pro- or anti-inflammatory activation. Therefore reducing MMP-14 activity and increasing that of TIMP-3 could be valid therapeutic approaches to reduce plaque rupture and myocardial infarction. PMID:25301980

Johnson, Jason L.; Jenkins, Nicholas P.; Huang, Wei-Chun; Sala-Newby, Graciela B.; Scholtes, Vincent P. W.; Moll, Frans L.; Pasterkamp, Gerard; Newby, Andrew C.

2014-01-01

190

A novel rat monoclonal antibody reactive with murine tumoricidal Kupffer cells and activated peritoneal macrophages from BCG-infected mice.  

PubMed Central

A rat monoclonal antibody, termed 1A2.10D and raised against mouse BCG-activated peritoneal-macrophages, was used to detect antigenic determinant(s) on mouse tumoricidal activated peritoneal and liver macrophages from BCG-infected mice by indirect immunofluorescence flow cytometry and immunoblot analysis. This antibody was of the rat IgG2b subclass and not cytolytic to BCG-activated macrophages in the presence of rabbit complement. The antigen(s) was expressed on tumoricidal activated peritoneal and liver macrophages from BCG-infected mice and some macrophage cell lines. Its expression could not be detected on resident peritoneal cells, peritoneal exudate cells containing non- or low tumoricidal macrophages, thymocytes, resting bone marrow cells, normal spleen cells, various established mouse tumour cells or one macrophage cell line. Immunoblot analysis showed the antibody to bind to one major protein of 56,000 MW, and to be expressed on the peritoneal and liver macrophages from BCG-infected mice. Using this antibody and a fluorescence-activated cell sorter, selection was made of antibody-positive or -negative macrophages from BCG-infected mice to examine their tumour killing activity. The antibody-positive macrophages clearly showed higher tumour killing activity than the negative macrophages. Images Figure 3 PMID:2420709

Someya, A

1986-01-01

191

Augmentation of macrophage growth-stimulating activity of lipids by their peroxidation  

SciTech Connect

Previously, we reported that some kinds of lipids (cholesterol esters, triglycerides, and some negatively charged phospholipids) that are constituents of lipoproteins or cell membranes induce growth of peripheral macrophages in vitro. In this paper, we examined the effect of peroxidation of lipids on their macrophage growth-stimulating activity because lipid peroxidation is observed in many pathological states such as inflammation. When phosphatidylserine, one of the phospholipids with growth-stimulating activity, was peroxidized by UV irradiation, its macrophage growth-stimulating activity was augmented in proportion to the extent of its peroxidation. The activity of phosphatidylethanolamine was also increased by UV irradiation. On the other hand, phosphatidylcholine or highly unsaturated free fatty acids, such as arachidonic acid and eicosapentaenoic acid, did not induce macrophage growth irrespective of whether they were peroxidized. The augmented activity of UV-irradiated phosphatidylserine was not affected by the coexistence of an antioxidant, vitamin E or BHT. These results suggest that some phospholipids included in damaged cells or denatured lipoproteins which are scavenged by macrophages in vivo may induce growth of peripheral macrophages more effectively when they are peroxidized by local pathological processes.

Yui, S.; Yamazaki, M. (Teikyo Univ., Kanagawa (Japan))

1990-02-15

192

Soluble factors produced by macrophages\\/monocytes inhibit lymphokine-activated killer activity in rat splenocyte cultures  

Microsoft Academic Search

In the present study we investigated the inhibition of interleukin-2(IL-2)-induced lymphokine-activated killer (LAK) activity in rat splenocyte cultures in relation to the presence of 2-mercaptoethanol and macrophages\\/monocytes. The presence of 2-mercaptoethanol is necessary for induction of LAK activity in rat splenocyte cultures. Removal of macrophages\\/monocytes from rat splenocytes by plastic or nylon-wool adherence, or iron ingestion resulted in LAK induction

Peter J. K. Kuppenl; Alexander M. M. Eggermont; Rianne B. W. M. Quakl; Andreas Marinelli; Gert Jan Fleurenl

1994-01-01

193

Differential macrophage activation alters the expression profile of NTPDase and ecto-5'-nucleotidase.  

PubMed

Macrophages are key elements in the inflammatory process, whereas depending on the micro-environmental stimulation they exhibit a pro-inflammatory (classical/M1) or an anti-inflammatory/reparatory (alternative/M2) phenotype. Extracellular ATP can act as a danger signal whereas adenosine generally serves as a negative feedback mechanism to limit inflammation. The local increase in nucleotides communication is controlled by ectonucleotidases, such as members of the ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) family and ecto-5'-nucleotidase/CD73 (ecto-5'-NT). In the present work we evaluated the presence of these enzymes in resident mice M1 (macrophages stimulated with LPS), and M2 (macrophages stimulated with IL-4) macrophages. Macrophages were collected by a lavage of the mice (6-8 weeks) peritoneal cavity and treated for 24 h with IL-4 (10 ng/mL) or LPS (10 ng/mL). Nitrite concentrations were measured using the Greiss reaction. Supernatants were harvested to determine cytokines and the ATPase, ADPase and AMPase activities were determined by the malachite green method and HPLC analysis. The expression of selected surface proteins was evaluated by flow cytometry. The results reveal that M1 macrophages presented a decreased ATP and AMP hydrolysis in agreement with a decrease in NTPDase1, -3 and ecto-5'-nucleotidase expression compared to M2. In contrast, M2 macrophages showed a higher ATP and AMP hydrolysis and increased NTPDase1, -3 and ecto-5'-nucleotidase expression compared to M1 macrophages. Therefore, macrophages of the M1 phenotype lead to an accumulation of ATP while macrophages of the M2 phenotype may rapidly convert ATP to adenosine. The results also showed that P1 and P2 purinoreceptors present the same mRNA profile in both phenotypes. In addition, M2 macrophages, which have a higher ATPase activity, were less sensitive to cell death. In conclusion, these changes in ectoenzyme activities might allow macrophages to adjust the outcome of the extracellular purinergic cascade in order to fine-tune their functions during the inflammatory set. PMID:22348056

Zanin, Rafael Fernandes; Braganhol, Elizandra; Bergamin, Letícia Scussel; Campesato, Luís Felipe Ingrassia; Filho, Alfeu Zanotto; Moreira, José Cláudio Fonseca; Morrone, Fernanda Bueno; Sévigny, Jean; Schetinger, Maria Rosa Chitolina; de Souza Wyse, Angela Terezinha; Battastini, Ana Maria Oliveira

2012-01-01

194

The M1 and M2 paradigm of macrophage activation: time for reassessment  

PubMed Central

Macrophages are endowed with a variety of receptors for lineage-determining growth factors, T helper (Th) cell cytokines, and B cell, host, and microbial products. In tissues, macrophages mature and are activated in a dynamic response to combinations of these stimuli to acquire specialized functional phenotypes. As for the lymphocyte system, a dichotomy has been proposed for macrophage activation: classic vs. alternative, also M1 and M2, respectively. In view of recent research about macrophage functions and the increasing number of immune-relevant ligands, a revision of the model is needed. Here, we assess how cytokines and pathogen signals influence their functional phenotypes and the evidence for M1 and M2 functions and revisit a paradigm initially based on the role of a restricted set of selected ligands in the immune response. PMID:24669294

2014-01-01

195

Similarity and Diversity in Macrophage Activation by Nematodes, Trematodes, and Cestodes  

PubMed Central

This review summarizes current knowledge of macrophages in helminth infections, with a focus not only on delineating the striking similarities in macrophage phenotype between diverse infections but also on highlighting the differences. Findings from many different labs illustrate that macrophages in helminth infection can act as anti-parasite effectors but can also act as powerful immune suppressors. The specific role for their alternative (Th2-mediated) activation in helminth killing or expulsion versus immune regulation remains to be determined. Meanwhile, the rapid growth in knowledge of alternatively activated macrophages will require an even more expansive view of their potential functions to include repair of host tissue and regulation of host metabolism. PMID:20145705

Jenkins, Stephen J.; Allen, Judith E.

2010-01-01

196

Lipin-1 Integrates Lipid Synthesis with Proinflammatory Responses during TLR Activation in Macrophages.  

PubMed

Lipin-1 is a Mg(2+)-dependent phosphatidic acid phosphatase involved in the de novo synthesis of phospholipids and triglycerides. Using macrophages from lipin-1-deficient animals and human macrophages deficient in the enzyme, we show in this work that this phosphatase acts as a proinflammatory mediator during TLR signaling and during the development of in vivo inflammatory processes. After TLR4 stimulation lipin-1-deficient macrophages showed a decreased production of diacylglycerol and activation of MAPKs and AP-1. Consequently, the generation of proinflammatory cytokines like IL-6, IL-12, IL-23, or enzymes like inducible NO synthase and cyclooxygenase 2, was reduced. In addition, animals lacking lipin-1 had a faster recovery from endotoxin administration concomitant with a reduced production of harmful molecules in spleen and liver. These findings demonstrate an unanticipated role for lipin-1 as a mediator of macrophage proinflammatory activation and support a critical link between lipid biosynthesis and systemic inflammatory responses. PMID:25252959

Meana, Clara; Peña, Lucía; Lordén, Gema; Esquinas, Esperanza; Guijas, Carlos; Valdearcos, Martín; Balsinde, Jesús; Balboa, María A

2014-11-01

197

ROS-Responsive Activatable Photosensitizing Agent for Imaging and Photodynamic Therapy of Activated Macrophages  

PubMed Central

The optical properties of macrophage-targeted theranostic nanoparticles (MacTNP) prepared from a Chlorin e6 (Ce6)-hyaluronic acid (HA) conjugate can be activated by reactive oxygen species (ROS) in macrophage cells. MacTNP are nonfluorescent and nonphototoxic in their native state. However, when treated with ROS, especially peroxynitrite, they become highly fluorescent and phototoxic. In vitro cell studies show that MacTNP emit near-infrared (NIR) fluorescence inside activated macrophages. The NIR fluorescence is quenched in the extracellular environment. MacTNP are nontoxic in macrophages up to a Ce6 concentration of 10 ?M in the absence of light. However, MacTNP become phototoxic upon illumination in a light dose-dependent manner. In particular, significantly higher phototoxic effect is observed in the activated macrophage cells compared to human dermal fibroblasts and non-activated macrophages. The ROS-responsive MacTNP, with their high target-to-background ratio, may have a significant potential in selective NIR fluorescence imaging and in subsequent photodynamic therapy of atherosclerosis with minimum side effects. PMID:24396511

Kim, Hyunjin; Kim, Youngmi; Kim, In-Hoo; Kim, Kyungtae; Choi, Yongdoo

2014-01-01

198

Fungicidal mechanisms of activated macrophages: evidence for nonoxidative mechanisms for killing of Blastomyces dermatitidis.  

PubMed

The mechanism(s) by which lymphokine-activated peritoneal macrophages kill Blastomyces dermatitidis was studied. Resident peritoneal macrophages from BALB/cByJ mice, when treated overnight with lymph node cells plus concanavalin A, supernatants from concanavalin A-stimulated spleen cells, or recombinant gamma interferon, were then able to kill a virulent B. dermatitidis isolate (ATCC 26199) (at levels of 25% +/- 4%, 28% +/- 8%, and 21% +/- 5%, respectively). Killing was not significantly decreased or enhanced in the presence of superoxide dismutase (450 U/ml), catalase (20,000 U/ml), dimethyl sulfoxide (300 mM), or azide (1 mM). Viable B. dermatitidis elicited a brisk oxidative burst and superoxide anion production in activated macrophages as measured by lucigenin-enhanced chemiluminescence, e.g., 10(4) cpm. However, these responses were not significantly different from those of control macrophages. Luminol-enhanced chemiluminescence responses by activated or control macrophages were meager (less than or equal to 10(2) cpm). These results indicate that activated macrophages kill B. dermatitidis by a mechanism(s) independent of products of the oxidative burst. PMID:3316037

Brummer, E; Stevens, D A

1987-12-01

199

Effect of cinnamon water extract on monocyte-to-macrophage differentiation and scavenger receptor activity  

PubMed Central

Background Water soluble cinnamon extract has been shown to increase insulin sensitivity and modulate macrophage activation, a desirable trait for the management of obesity or atherosclerosis. Our present study investigated whether cinnamon water extract (CWE) may influence the differentiation of monocytes into macrophages and the activity of macrophage scavenger receptors, commonly observed in atherosclerotic lesions. Methods We investigated the effect of CWE on the expression of various surface markers and the uptake of acetylated low density lipoprotein (LDL) in phorbol-12-myristate-13-acetate (PMA)-stimulated THP-1 cells. The protein levels of PMA or macrophage-colony stimulating factor (M-CSF)-stimulated type 1 macrophage scavenger receptor (SRA) were analyzed. Finally, the role of extracellar signal-related kinase (ERK) 1/2 in SRA synthesis and the effect of CWE on PMA-stimulated ERK1/2 were determined. Results CWE inhibited the differentiation of monocyte by decreasing the expression of CD11b, CD36 and SRA and the uptake of acetyl LDL. CWE suppressed the upregulation of SRA by M-CSF and modulated ERK1/2 activity, which was required for PMA-induced SRA synthesis. Conclusions Our results demonstrate that CWE was able to interfere with monocyte differentiation and macrophage scavenger activity, indicating its potential in preventing the development of atherosclerotic lesions. PMID:24602512

2014-01-01

200

Chaperone-like activity of macrophage migration inhibitory factor  

Microsoft Academic Search

Macrophage migration inhibitory factor is a ubiquitous multifunctional cytokine having diverse immunological and neuroendocrine properties. Although this protein is known to be released into the circulation from the secretory granules of anterior pituitary or directly from immune cells as a consequence of stress, its participation in heat stress-induced aggregation of proteins has not yet been reported. We provide here the

Oxana A. Cherepkova; Elena M. Lyutova; Tatyana B. Eronina; Bella Ya. Gurvits

2006-01-01

201

Inhibition of 5-Lipoxygenase Pathway Attenuates Acute Liver Failure by Inhibiting Macrophage Activation  

PubMed Central

This study aimed to investigate the role of 5-lipoxygenase (5-LO) in acute liver failure (ALF) and changes in macrophage activation by blocking it. ALF was induced in rats by administration of D-galactosamine (D-GalN)/lipopolysaccharide (LPS). Rats were injected intraperitoneally with AA-861 (a specific 5-LO inhibitor), 24?hr before D-GalN/LPS administration. After D-GalN/LPS injection, the liver tissue was collected for assessment of histology, macrophage microstructure, macrophage counts, 5-LO mRNA formation, protein expression, and concentration of leukotrienes. Serum was collected for detecting alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin (Tbil), and tumor necrosis factor- (TNF-)?. Twenty-four hours after injection, compared with controls, ALF rats were characterized by widespread hepatocyte necrosis and elevated ALT, AST, and Tbil, and 5-LO protein expression reached a peak. Liver leukotriene B4 was also significantly elevated. However, 5-LO mRNA reached a peak 8?hr after D-GalN/LPS injection. Simultaneously, the microstructure of macrophages was changed most significantly and macrophages counts were increased significantly. Moreover, serum TNF-? was also elevated. By contrast, AA-861 pretreatment significantly decreased liver necrosis as well as all of the parameters compared with the rats without pretreatment. Macrophages, via the 5-LO pathway, play a critical role in ALF, and 5-LO inhibitor significantly alleviates ALF, possibly related to macrophage inhibition. PMID:24987711

Li, Lu; Liu, Yi-Rong; Li, Jun-Feng; Li, Shan-Shan; Zhang, Dan-Dan; Liu, Shuang; Bai, Li; Zheng, Su-Jun; Duan, Zhong-Ping; Chen, Yu

2014-01-01

202

Investigation of the component of Propionibacterium acnes (Corynebacterium parvum) responsible for macrophage activation.  

PubMed Central

Mouse peritoneal macrophages, activated with Propionibacterium acnes (Corynebacterium parvum) in vivo, exhibited altered morphological characteristics, increased acid phosphatase activity, and release of [EH]thymidine-labeled DNA from tumor cells in vitro. Comparison with macrophages from mice injected with a control organism, P. jensenii, showed that the morphological changes, but not acid phosphatase, correlated with the development of tumoricidal activity. Investigation of the microbial component responsible for this activity indicated it was heat stable and refractory to extraction by methanol-chloroform, dilute acid, butanol, or a serial combination of extraction procedures. When the cells were disrupted by mechanical breakage, no activity could be found in the cell wall, soluble cytoplasm, or particulate cytoplasm. These results suggest that intact organisms are required for macrophage activation, and they may resolve conflicting reports on the nature of the immunostimulating activity of P. acnes. Images Fig. 1 PMID:7380542

Buck, G E; Kelly, M T

1980-01-01

203

Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury  

PubMed Central

Background Previous studies have shown beneficial effects of mesenchymal stem cell (MSC) transplantation in central nervous system (CNS) injuries, including traumatic brain injury (TBI). Potential repair mechanisms involve transdifferentiation to replace damaged neural cells and production of growth factors by MSCs. However, few studies have simultaneously focused on the effects of MSCs on immune cells and inflammation-associated cytokines in CNS injury, especially in an experimental TBI model. In this study, we investigated the anti-inflammatory and immunomodulatory properties of MSCs in TBI-induced neuroinflammation by systemic transplantation of MSCs into a rat TBI model. Methods/results MSCs were transplanted intravenously into rats 2 h after TBI. Modified neurologic severity score (mNSS) tests were performed to measure behavioral outcomes. The effect of MSC treatment on neuroinflammation was analyzed by immunohistochemical analysis of astrocytes, microglia/macrophages, neutrophils and T lymphocytes and by measuring cytokine levels [interleukin (IL)-1?, IL-1?, IL-4, IL-6, IL-10, IL-17, tumor necrosis factor-?, interferon-?, RANTES, macrophage chemotactic protein-1, macrophage inflammatory protein 2 and transforming growth factor-?1] in brain homogenates. The immunosuppression-related factors TNF-? stimulated gene/protein 6 (TSG-6) and nuclear factor-?B (NF-?B) were examined by reverse transcription-polymerase chain reaction and Western blotting. Intravenous MSC transplantation after TBI was associated with a lower density of microglia/macrophages and peripheral infiltrating leukocytes at the injury site, reduced levels of proinflammatory cytokines and increased anti-inflammatory cytokines, possibly mediated by enhanced expression of TSG-6, which may suppress activation of the NF-?B signaling pathway. Conclusions The results of this study suggest that MSCs have the ability to modulate inflammation-associated immune cells and cytokines in TBI-induced cerebral inflammatory responses. This study thus offers a new insight into the mechanisms responsible for the immunomodulatory effect of MSC transplantation, with implications for functional neurological recovery after TBI. PMID:23971414

2013-01-01

204

Inflammatory Activation of Arachidonic Acid Signaling in Murine P388D1 Macrophages via Sphingomyelin Synthesis*  

E-print Network

the AA liberated by the sPLA2 (3, 5, 7). In P388D1 macrophages (7) and mast cells as well (4, 5), this s- rangement has been proposed for macrophages (3) and later confirmed to also occur in mast cells (6). cPLA2 intracellularly (3). Thus, quantitation of extracellular AA re- lease in activated P388D1 cells correlates best

Dennis, Edward A.

205

Macrophage derived platelet activating factor implicated in the resolution phase of gouty inflammation.  

PubMed

Human blood derived in vitro differentiated monocytes or macrophages are a population of cells which have been investigated over the years to determine the role these cells play in the resolution phase of gout. Macrophages are able to phagocytose monosodium urate monohydrate (MSU) crystals without releasing inflammatory factors. This study analysed macrophage platelet activating factor secretion and its possible role in the pathway of gout resolution. Analysis of sunatants from in vitro differentiated macrophages stimulated with MSU crystals revealed the secretion of platelet activating factor (PAF)??1.54 ± 0.10 mean ± SEM;?ng/mL per 10(6) cells. This secretion was absent in immature monocytes treated similarly. When these monocytes were pretreated with recombinant human PAF-acetylhydrolase (rhuPAF-AH) and MSU crystals resulted in TNF? suppression. Addition of WEB2086, a platelet activating factor (PAF) antagonist, to differentiated macrophages with MSU crystals unmasked TNF? secretion 0.7 ± 0.06 mean ± SEM;?ng/mL per 10(6) cells. This study identifies a role for PAF and the PAF receptor antagonist in the pathway by which macrophages ingest MSU crystals and resolve the concomitant inflammation. PMID:25328755

Yagnik, Darshna

2014-01-01

206

Direct Effects of Activin A on the Activation of Mouse Macrophage RAW264.7 Cells  

PubMed Central

Macrophages play critical roles in innate immune and acquired immune via secreting pro-inflammatory mediators, phagocytosing microorganisms and presenting antigens. Activin A, a member of transforming growth factor ? (TGF-?) superfamily, is produced by macrophages and microglia cells. In this study, we reported a direct effect of activin A as a pro-inflammatory factor on mouse macrophage cell line RAW264.7 cells. Our data revealed that activin A could not only increase IL-1? and IL-6 production from RAW264.7 cells, but also promote pinocytic and phagocytic activities of RAW264.7 cells. In addition, activin A obviously up-regulated MHC II expression on the surface of RAW264.7 cells, whereas did not influence MHC I expression. Activin A also enhanced CD80 expression, which is a marker of activated macrophages, but did not influence RAW264.7 cell proliferation. These data suggest that activin A may regulate primary macrophage-mediated innate and acquired immune response via promoting the activation of rest macrophages. PMID:19403063

Ge, Jingyan; Wang, Yinan; Feng, Ye; Liu, Haiyan; Cui, Xueling; Chen, Fangfang; Tai, Guixiang; Liu, Zhonghui

2009-01-01

207

Macrophage Derived Platelet Activating Factor Implicated in the Resolution Phase of Gouty Inflammation  

PubMed Central

Human blood derived in vitro differentiated monocytes or macrophages are a population of cells which have been investigated over the years to determine the role these cells play in the resolution phase of gout. Macrophages are able to phagocytose monosodium urate monohydrate (MSU) crystals without releasing inflammatory factors. This study analysed macrophage platelet activating factor secretion and its possible role in the pathway of gout resolution. Analysis of sunatants from in vitro differentiated macrophages stimulated with MSU crystals revealed the secretion of platelet activating factor (PAF)??1.54 ± 0.10 mean ± SEM;?ng/mL per 106 cells. This secretion was absent in immature monocytes treated similarly. When these monocytes were pretreated with recombinant human PAF-acetylhydrolase (rhuPAF-AH) and MSU crystals resulted in TNF? suppression. Addition of WEB2086, a platelet activating factor (PAF) antagonist, to differentiated macrophages with MSU crystals unmasked TNF? secretion 0.7 ± 0.06 mean ± SEM;?ng/mL per 106 cells. This study identifies a role for PAF and the PAF receptor antagonist in the pathway by which macrophages ingest MSU crystals and resolve the concomitant inflammation. PMID:25328755

2014-01-01

208

Caspase-8 prevents sustained activation of NF-kappaB in monocytes undergoing macrophagic differentiation  

PubMed Central

Caspases have demonstrated several non-apoptotic functions including a role in the differentiation of specific cell types. Here, we show that caspase-8 is the upstream enzyme in the proteolytic caspase cascade whose activation is required for the differentiation of peripheral blood monocytes into macrophages. Upon Macrophage Colony Stimulating Factor (M-CSF) exposure, caspase-8 associates with the adaptor protein Fas-Associated Death Domain (FADD), the serine/threonine kinase Receptor-Interacting-Protein 1 (RIP1) and the long isoform of FLICE-inhibitory protein FLIP. Overexpression of FADD accelerates the differentiation process that does not involve any death receptor. Active caspase-8 cleaves RIP1, which prevents sustained NF-?B activation, and activates downstream caspases. Altogether, these data identify a role for caspase-8 in monocytes undergoing macrophagic differentiation, i.e. the enzyme activated in an atypical complex down-regulates NF-?B activity through RIP1 cleavage. PMID:17047155

Rebe, Cedric; Cathelin, Severine; Launay, Sophie; Filomenko, Rodolphe; Prevotat, Laurent; L'Ollivier, Coralie; Gyan, Emmanuel; Micheau, Olivier; Grant, Steven; Dubart-Kupperschmitt, Anne; Fontenay, Michaela; Solary, Eric

2007-01-01

209

IFN-?-activated lymphocytes boost nitric oxide production in grass carp monocytes/macrophages.  

PubMed

It is well known that IFN-? is a prime activator of nitric oxide (NO) production by monocytes/macrophages in mammals and fish. In parallel, whether IFN-?-activated lymphocytes are associated with NO production remains unclear. In this study, grass carp monocytes/macrophages and lymphocytes from head kidney were isolated and effects of recombinant grass carp IFN-? (rgcIFN-?) on NO releases by these two cell populations were determined. Results showed that rgcIFN-? time- and dose-dependently increased NO production by monocytes/macrophages but not lymphocytes, which are consistent with the findings in mammals. Interestingly, rgcIFN-? displayed a greater stimulation on NO production in the co-cultures of monocytes/macrophages and lymphocytes when compared with that in the culture of monocytes/macrophages alone. Furthermore, the media harvested from rgcIFN-?-treated lymphocytes were effective in boosting NO release in monocytes/macrophages. These data suggest that secretions from rgcIFN-?-treated lymphocytes may be involved in the NO release by monocytes/macrophages. To address this hypothesis, effect of rgcIFN-? on the gene expression of inflammatory cytokines in grass carp lymphocytes was examined, showing that it consistently stimulated the mRNA expression of grass carp TNF-? and IL-1? but not IFN-?. Furthermore, treatment of rgcIFN-? combined with recombinant grass carp IL-1? (rgcIL-1?) induced a NO production by monocytes/macrophages, which was significantly higher than those induced by either cytokine alone. It provides the evidence that the cytokines secreted by the activated lymphocytes may facilitate the NO production by monocytes/macrophages. Taken together, our findings point out a new mechanism for the involvement of IFN-?-activated lymphocytes in the NO production by monocytes/macrophages in fish. This knowledge not only strengthens the role of IFN-? in immune system but also provides the evidence for the existence of a close relationship between lymphocytes and monocytes/macrophages in fish. PMID:24056277

Yang, Kun; Zhang, Shengnan; Chen, Danyan; Zhang, Anying; Wang, Xinyan; Zhou, Hong

2013-11-01

210

Iron down-regulates macrophage anti-tumour activity by blocking nitric oxide production  

PubMed Central

Although the inhibitory effect of iron on macrophage production of tumoricidal free radical nitric oxide (NO) has been reported, its possible influence on macrophage anti-tumour activity has not been established. In the present study, FeSO4 markedly reduced IFN-? + LPS-induced NO synthesis in mouse and rat macrophages. The effect of iron coincided with the loss of macrophage cytotoxic activity against NO-sensitive C6 rat astrocytoma and L929 mouse fibrosarcoma cell lines, as measured by MTT assay for cellular respiration and the crystal violet test for cell viability. Tumour cell survival did not improve further in the presence of FeSO4 if macrophage NO release and cytotoxicity were already blocked by aminoguanidine. In accordance with the results obtained with exogenous iron, cell membrane permeable iron chelator o-phenanthroline enhanced both macrophage NO release and anti-tumour activity. Iron also down-regulated NO production and increased the viability of L929 fibrosarcoma cells stimulated with IFN-? + LPS in the absence of macrophages. However, neither NO release nor cell viability was affected by iron addition to cultures of the C6 astrocytoma cell line. Iron was unable to prevent L929 and C6 cell death induced by the NO releasing chemicals SNP and SIN-1, indicating that iron-mediated inhibition of NO synthesis, rather than interference with its cytotoxic action, was responsible for the protection of tumour cells. Collectively, these results indicate that iron might protect tumour cells by reducing both macrophage and tumour cell-derived NO release. PMID:15196250

HARHAJI, L; VUCKOVIC, O; MILJKOVIC, D; STOSIC-GRUJICIC, S; TRAJKOVIC, V

2004-01-01

211

Analysis of the primed intermediate stage in the macrophage tumoricidal activation pathway  

SciTech Connect

Model systems were developed for the analysis of macrophage activation for tumor cell killing using established murine macrophage-like tumor cell lines. This activation process is currently understood as consisting of sequential priming and triggering steps. Treatment with interferon-gamma resulted in the acquisition of a primed activation state by some, but not all, of the macrophage populations studied. A dissociation of the modulation of cell surface major histocompatibility complex (MHC) Class II (Ia) antigen expression and priming for tumor cytolysis by interferon-gamma was observed in the macrophage cell lines, indicating that the primed intermediate in the macrophage tumoricidal activation pathway was not necessarily Ia antigen-positive. Examination of the tumor cytolytic activity of cycloheximide-treated cells indicated that protein synthesis was required for priming by interferon-gamma. A novel priming stimulus, gamma irradiation, was identified using the RAW 264.7 cell line. Treatment of the RAW 264.7 cell line with doses of gamma radiation > 1000 rads resulted in the acquisition of the primed intermediate activation state, as evidenced by the expression of maximum tumor cell killing following incubation of irradiated cells with the triggering stimulus alone.

Lambert, L.E.

1987-01-01

212

Moxibustion Activates Macrophage Autophagy and Protects Experimental Mice against Bacterial Infection  

PubMed Central

Moxibustion is one of main therapies in traditional Chinese medicine and uses heat stimulation on the body surface from the burning of moxa to release pain or treat diseases. Emerging studies have shown that moxibustion can generate therapeutic effects by activating a series of signaling pathways and neuroendocrine-immune activities. Here we show moxibustion promoted profound macrophage autophagy in experimental Kunming mice, with reduced Akt phosphorylation and activated eIF2? phosphorylation. Consequently, moxibustion promoted bacterial clearance by macrophages and protected mice from mortality due to bacterial infection. These results indicate that moxibustion generates a protective response by activating autophagy against bacterial infections. PMID:25140186

Li, Xiaojuan; Guo, Guanhua; Shen, Feng; Kong, Lihong; Liang, Fengxia; Sun, Guojie

2014-01-01

213

Inhibition of Nuclear Factor-Kappa B Activation Decreases Survival of Mycobacterium tuberculosis in Human Macrophages  

PubMed Central

Nuclear factor-kappa B (NF?B) is a ubiquitous transcription factor that mediates pro-inflammatory responses required for host control of many microbial pathogens; on the other hand, NF?B has been implicated in the pathogenesis of other inflammatory and infectious diseases. Mice with genetic disruption of the p50 subunit of NF?B are more likely to succumb to Mycobacterium tuberculosis (MTB). However, the role of NF?B in host defense in humans is not fully understood. We sought to examine the role of NF?B activation in the immune response of human macrophages to MTB. Targeted pharmacologic inhibition of NF?B activation using BAY 11-7082 (BAY, an inhibitor of I?B? kinase) or an adenovirus construct with a dominant-negative I?B? significantly decreased the number of viable intracellular mycobacteria recovered from THP-1 macrophages four and eight days after infection. The results with BAY were confirmed in primary human monocyte-derived macrophages and alveolar macrophages. NF?B inhibition was associated with increased macrophage apoptosis and autophagy, which are well-established killing mechanisms of intracellular MTB. Inhibition of the executioner protease caspase-3 or of the autophagic pathway significantly abrogated the effects of BAY. We conclude that NF?B inhibition decreases viability of intracellular MTB in human macrophages via induction of apoptosis and autophagy. PMID:23634218

Chmura, Kathryn; Ovrutsky, Alida R.; Su, Wen-Lin; Griffin, Laura; Pyeon, Dohun; McGibney, Mischa T.; Strand, Matthew J.; Numata, Mari; Murakami, Seiji; Gaido, Loretta; Honda, Jennifer R.; Kinney, William H.; Oberley-Deegan, Rebecca E.; Voelker, Dennis R.; Ordway, Diane J.; Chan, Edward D.

2013-01-01

214

Allergens as immunomodulatory proteins: the cat dander protein Fel d 1 enhances TLR activation by lipid ligands.  

PubMed

Allergic responses can be triggered by structurally diverse allergens. Most allergens are proteins, yet extensive research has not revealed how they initiate the allergic response and why the myriad of other inhaled proteins do not. Among these allergens, the cat secretoglobulin protein Fel d 1 is a major allergen and is responsible for severe allergic responses. In this study, we show that similar to the mite dust allergen Der p 2, Fel d 1 substantially enhances signaling through the innate receptors TLR4 and TLR2. In contrast to Der p 2, however, Fel d 1 does not act by mimicking the TLR4 coreceptor MD2 and is not able to bind stably to the TLR4/MD2 complex in vitro. Fel d 1 does, however, bind to the TLR4 agonist LPS, suggesting that a lipid transfer mechanism may be involved in the Fel d 1 enhancement of TLR signaling. We also show that the dog allergen Can f 6, a member of a distinct class of lipocalin allergens, has very similar properties to Fel d 1. We propose that Fel d 1 and Can f 6 belong to a group of allergen immunomodulatory proteins that enhance innate immune signaling and promote airway hypersensitivity reactions in diseases such as asthma. PMID:23878318

Herre, Jurgen; Grönlund, Hans; Brooks, Heather; Hopkins, Lee; Waggoner, Lisa; Murton, Ben; Gangloff, Monique; Opaleye, Olaniyi; Chilvers, Edwin R; Fitzgerald, Kate; Gay, Nick; Monie, Tom; Bryant, Clare

2013-08-15

215

Targeting GGTase-I Activates RHOA, Increases Macrophage Reverse Cholesterol Transport, and Reduces Atherosclerosis in Mice  

PubMed Central

Background Statins have antiinflammatory and antiatherogenic effects that have been attributed to inhibition of RHO protein geranylgeranylation in inflammatory cells. The activity of protein geranylgeranyltransferase type I (GGTase-I) is widely believed to promote membrane association and activation of RHO family proteins. However, we recently showed that knockout of GGTase-I in macrophages activates RHO proteins and proinflammatory signaling pathways, leading to increased cytokine production and rheumatoid arthritis. In this study, we asked whether the increased inflammatory signaling of GGTase-I–deficient macrophages would influence the development of atherosclerosis in low-density lipoprotein receptor–deficient mice. Methods and Results Aortic lesions in mice lacking GGTase-I in macrophages (Pggt1b?/?) contained significantly more T lymphocytes than the lesions in controls. Surprisingly, however, mean atherosclerotic lesion area in Pggt1b?/? mice was reduced by ?60%. GGTase-I deficiency reduced the accumulation of cholesterol esters and phospholipids in macrophages incubated with minimally modified and acetylated low-density lipoprotein. Analyses of GGTase-I–deficient macrophages revealed upregulation of the cyclooxygenase 2–peroxisome proliferator-activated-? pathway and increased scavenger receptor class B type I– and CD36-mediated basal and high-density lipoprotein–stimulated cholesterol efflux. Lentivirus-mediated knockdown of RHOA, but not RAC1 or CDC42, normalized cholesterol efflux. The increased cholesterol efflux in cultured cells was accompanied by high levels of macrophage reverse cholesterol transport and slightly reduced plasma lipid levels in vivo. Conclusions Targeting GGTase-I activates RHOA and leads to increased macrophage reverse cholesterol transport and reduced atherosclerosis development despite a significant increase in inflammation. PMID:23334894

Khan, Omar M.; Akula, Murali K.; Skålen, Kristina; Karlsson, Christin; Ståhlman, Marcus; Young, Stephen G.; Borén, Jan; Bergo, Martin O.

2013-01-01

216

Induction of bone formation by activated monocytes / macrophages depends on Oncostatin M signaling  

E-print Network

) activation by lipopolysaccharide or endogenous ligands, OSM was produced in classically activated induced by monocytes/macrophages and TLRs activation: IL-6 and Leukemia inhibitory factor. We propose and TLR ligands stimulates bone formation that is largely uncoupled from bone resorption and is thus

Boyer, Edmond

217

Inhibitors of the 5-lipoxygenase pathway activate pannexin1 channels in macrophages via the thromboxane receptor.  

PubMed

A multitude of environmental signaling molecules influence monocyte and macrophage innate and adaptive immune responses, including ATP and prostanoids. Interestingly, purinergic (P2) and eicosanoid receptor signaling interact such that the activation of P2 receptors leads to prostanoid production, which can then interfere with P2Y-mediated macrophage migration. Recent studies suggest that blockade of 5-lipoxygenase (5-LOX) in macrophages can activate a permeation pathway involved in the influx of dye and the release of ATP. Here, we provide evidence that pannexin1 (Panx1) is a component of this pathway and present the intracellular signaling molecules linking the thromboxane (TP) receptor to Panx1-mediated dye influx and ATP release. Using pharmacological tools and transgenic mice deficient in Panx1, we show that two 5-LOX pathway inhibitors induce ATP release and influx of dye in a Panx1-dependent manner. Electrophysiological recordings performed in wild-type and Panx1-deficient macrophages confirmed that these 5-LOX pathway inhibitors activate currents characteristic of Panx1 channels. We found that the mechanism by which Panx1 channels are activated under this condition involves activation of the TP receptor that is mediated by the cAMP/PKA pathway. This is to our knowledge the first evidence for the involvement of Panx1 in the TP receptor signaling pathway. Future studies aimed to clarify the contribution of this TP-Panx1 signaling network to macrophage immune responses are likely to be important for targeting inflammatory and autoimmune diseases. PMID:25080488

da Silva-Souza, Hercules A; de Lira, Maria Nathália; Patel, Naman K; Spray, David C; Persechini, Pedro Muanis; Scemes, Eliana

2014-09-15

218

Immunocytochemical localization of latent transforming growth factor-beta1 activation by stimulated macrophages  

NASA Technical Reports Server (NTRS)

Transforming growth factor-beta1 (TGF-beta) is secreted in a latent form consisting of mature TGF-beta noncovalently associated with its amino-terminal propeptide, which is called latency associated peptide (LAP). Biological activity depends upon the release of TGF-beta from the latent complex following extracellular activation, which appears to be the key regulatory mechanism controlling TGF-beta action. We have identified two events associated with latent TGF-beta (LTGF-beta) activation in vivo: increased immunoreactivity of certain antibodies that specifically detect TGF-beta concomitant with decreased immunoreactivity of antibodies to LAP. Macrophages stimulated in vitro with interferon-gamma and lipopolysaccharide reportedly activate LTGF-beta via cell membrane-bound protease activity. We show through dual immunostaining of paraformaldehyde-fixed macrophages that such physiological TGF-beta activation is accompanied by a loss of LAP immunoreactivity with concomitant revelation of TGF-beta epitopes. The induction of TGF-beta immunoreactivity colocalized with immunoreactive betaglycan/RIII in activated macrophages, suggesting that LTGF-beta activation occurs on the cell surface. Confocal microscopy of metabolically active macrophages incubated with antibodies to TGF-beta and betaglycan/RIII prior to fixation supported the localization of activation to the cell surface. The ability to specifically detect and localize LTGF-beta activation provides an important tool for studies of its regulation.

Chong, H.; Vodovotz, Y.; Cox, G. W.; Barcellos-Hoff, M. H.; Chatterjee, A. (Principal Investigator)

1999-01-01

219

Immunocytochemical Localization of Latent Transforming Growth Factor-B1 Activation by Stimulated Macrophages  

SciTech Connect

Transforming growth factor-{beta}1 (TGF-{beta}) is secreted in a latent form consisting of mature TGF-{beta} noncovalently associated with its amino-terminal propeptide, which is called latency associated peptide (LAP). Biological activity depends upon the release of TGF-{beta} from the latent complex following extracellular activation, which appears to be the key regulatory mechanism controlling TGF-{beta} action. We have identified two events associated with latent TGF-{beta} (LTGF-{beta}) activation in vivo: increased immunoreactivity of certain antibodies that specifically detect TGF-{beta} concomitant with decreased immunoreactivity of antibodies to LAP. Macrophages stimulated in vitro with interferon-{gamma} and lipopolysaccharide reportedly activate LTGF-{beta} via cell membrane-bound protease activity. We show through dual immunostaining of paraformaldehyde-fixed macrophages that such physiological TGF-{beta} activation is accompanied by a loss of LAP immunoreactivity with concomitant revelation of TGF-{beta} epitopes. The induction of TGF-{beta} immunoreactivity colocalized with immunoreactive betaglycan/RIII in activated macrophages, suggesting that LTGF-{beta} activation occurs on the cell surface. Confocal microscopy of metabolically active macrophages incubated with antibodies to TGF-{beta} and betaglycan/RIII prior to fixation supported the localization of activation to the cell surface. The ability to specifically detect and localize LTGF-{beta} activation provides an important tool for studies of its regulation.

Chong, Hyonkyong; Vodovotz, Yoram; Cox, G.W.; Barcellos-Hoff, M.H.

1998-09-22

220

Polyoxygenated Cholesterol Ester Hydroperoxide Activates TLR4 and SYK Dependent Signaling in Macrophages  

PubMed Central

Oxidation of low-density lipoprotein (LDL) is one of the major causative mechanisms in the development of atherosclerosis. In previous studies, we showed that minimally oxidized LDL (mmLDL) induced inflammatory responses in macrophages, macropinocytosis and intracellular lipid accumulation and that oxidized cholesterol esters (OxCEs) were biologically active components of mmLDL. Here we identified a specific OxCE molecule responsible for the biological activity of mmLDL and characterized signaling pathways in macrophages in response to this OxCE. Using liquid chromatography – tandem mass spectrometry and biological assays, we identified an oxidized cholesteryl arachidonate with bicyclic endoperoxide and hydroperoxide groups (BEP-CE) as a specific OxCE that activates macrophages in a TLR4/MD-2-dependent manner. BEP-CE induced TLR4/MD-2 binding and TLR4 dimerization, phosphorylation of SYK, ERK1/2, JNK and c-Jun, cell spreading and uptake of dextran and native LDL by macrophages. The enhanced macropinocytosis resulted in intracellular lipid accumulation and macrophage foam cell formation. Bone marrow-derived macrophages isolated from TLR4 and SYK knockout mice did not respond to BEP-CE. The presence of BEP-CE was demonstrated in human plasma and in the human plaque material captured in distal protection devices during percutaneous intervention. Our results suggest that BEP-CE is an endogenous ligand that activates the TLR4/SYK signaling pathway. Because BEP-CE is present in human plasma and human atherosclerotic lesions, BEP-CE-induced and TLR4/SYK-mediated macrophage responses may contribute to chronic inflammation in human atherosclerosis. PMID:24376657

Choi, Soo-Ho; Yin, Huiyong; Ravandi, Amir; Armando, Aaron; Dumlao, Darren; Kim, Jungsu; Almazan, Felicidad; Taylor, Angela M.; McNamara, Coleen A.; Tsimikas, Sotirios; Dennis, Edward A.; Witztum, Joseph L.; Miller, Yury I.

2013-01-01

221

Binding and activation of major histocompatibility complex class II-deficient macrophages by staphylococcal exotoxins  

NASA Technical Reports Server (NTRS)

Macrophages from C2D transgenic mice deficient in the expression of major histocompatibility complex (MHC) class II proteins were used to identify binding sites for superantigens distinct from the MHC class II molecule. Iodinated staphylococcal enterotoxins A and B (SEA and SEB) and exfoliative toxins A and B (ETA and ETB) bound to C2D macrophages in a concentration-dependent and competitive manner. All four toxins increased F-actin concentration within 30 s of their addition to C2D macrophages, indicating that signal transduction occurred in response to toxin in the absence of class II MHC. Furthermore, ETA, ETB, SEA, and, to a lesser extent, SEB induced C2D macrophages to produce interleukin 6. Several molecular species on C2D macrophages with molecular masses of 140, 97, 61, 52, 43, and 37 kDa bound SEA in immunoprecipitation experiments. These data indicate the presence of novel, functionally active toxin binding sites on murine macrophages distinct from MHC class II molecules.

Beharka, A. A.; Armstrong, J. W.; Iandolo, J. J.; Chapes, S. K.; Spooner, B. S. (Principal Investigator)

1994-01-01

222

Macrophage activation, phagocytosis and intracellular calcium oscillations induced by scorpion toxins from Tityus serrulatus  

PubMed Central

The research described here is focused upon studying the activation of mice peritoneal macrophages when submitted to in vitro effects of Tityus serrulatus scorpion venom and its major toxic peptides. Several functional events were analysed, such as: cytotoxicity, spreading, extent of phagocytosis, vacuole formation and changes of internal calcium concentration. Among the main results observed, when macrophages are subjected to the effects of soluble venom of Tityus serrulatus scorpion venom, a partially purified fraction (FII) or a pure toxin (Ts1), are an increment in the percentage of phagocytosis and vacuole formation, a decrement of the spreading ability, accompanied by oscillations of internal calcium concentration. The net results demonstrate that scorpion venom or its major toxins are effective stimulators of macrophage activity; the effect of whole soluble venom or partially purified fractions is due to the toxic peptides, seen here clearly with Ts1. The possible involvement of Na+-channels in these events is discussed. A basic understanding of the underlying molecular mechanisms responsible for macrophage activation should serve as a foundation for novel drug development aimed at modulating macrophage activity. PMID:19037924

Petricevich, V L; Reynaud, E; Cruz, A H; Possani, L D

2008-01-01

223

Folate Receptor-? in Activated Macrophages: Ligand Binding and Receptor Recycling Kinetics.  

PubMed

Activated macrophages overexpress a receptor for the vitamin folic acid termed the folate receptor ? (FR-?). Because conjugation of folate to low molecular weight drugs, genes, liposomes, nanoparticles, and imaging agents has minor effects on FR binding, the vitamin can be exploited to target both therapeutic and imaging agents to activated macrophages without promoting their uptake by other healthy cells. In this paper, we characterize the binding, internalization, and recycling kinetics of FR-? on activated macrophages in inflamed tissues of rats with adjuvant-induced arthritis. Our results demonstrate that saturation of macrophage FR is achieved at injection doses of ?150-300 nmol/kg, with more rapidly perfused tissues saturating at lower doses than inflamed appendages. After binding, FR-? internalizes and recycles back to the cell surface every ?10-20 min, providing empty receptors for additional folate conjugate uptake. Because the half-life of low molecular weight folate conjugates in the vasculature is usually <1 h, these data suggest that targeting of folate conjugates to activated macrophages in vivo can be maximized by frequent dosing at conjugate concentrations that barely saturate FR (?150 nmol/kg), thereby minimizing nonspecific binding to receptor-negative tissues and maximizing the probability that unoccupied cell surface receptors will be exposed to folate-drug conjugate. PMID:25166491

Varghese, Bindu; Vlashi, Erina; Xia, Wei; Ayala Lopez, Wilfredo; Paulos, Chrystal M; Reddy, Joseph; Xu, Le-Cun; Low, Philip S

2014-10-01

224

Classically activated macrophages use stable microtubules for matrix metalloproteinase-9 (MMP-9) secretion.  

PubMed

As major effector cells of the innate immune response, macrophages must adeptly migrate from blood to infected tissues. Endothelial transmigration is accomplished by matrix metalloproteinase (MMP)-induced degradation of basement membrane and extracellular matrix components. The classical activation of macrophages with LPS and IFN-? causes enhanced microtubule (MT) stabilization and secretion of MMPs. Macrophages up-regulate MMP-9 expression and secretion upon immunological challenge and require its activity for migration during the inflammatory response. However, the dynamics of MMP-9 production and intracellular distribution as well as the mechanisms responsible for its trafficking are unknown. Using immunofluorescent imaging, we localized intracellular MMP-9 to small Golgi-derived cytoplasmic vesicles that contained calreticulin and protein-disulfide isomerase in activated RAW 264.7 macrophages. We demonstrated vesicular organelles of MMP-9 aligned along stable subsets of MTs and showed that selective modulation of MT dynamics contributes to the enhanced trafficking of MMP-9 extracellularly. We found a Rab3D-dependent association of MMP-9 vesicles with the molecular motor kinesin, whose association with the MT network was greatly enhanced after macrophage activation. Finally, we implicated kinesin 5B and 3B isoforms in the effective trafficking of MMP-9 extracellularly. PMID:22270361

Hanania, Raed; Sun, He Song; Xu, Kewei; Pustylnik, Sofia; Jeganathan, Sujeeve; Harrison, Rene E

2012-03-01

225

In vivo anti-influenza virus activity of an immunomodulatory acidic polysaccharide isolated from Cordyceps militaris grown on germinated soybeans.  

PubMed

An acidic polysaccharide (APS) was isolated from the extract of Cordyceps militaris grown on germinated soybeans. Analyses of sugar composition indicated that APS consisted of d-galactose, L-arabinose, D-xylose, L-rhamnose, and D-galacturonic acid. On the basis of the result of methylation analysis, APS was considered to be mainly composed of Araf-(1-->, -->5)-Araf-(1-->, -->4)-Galp-(1--> and -->4)-GalAp-(1--> residues. When the polysaccharide was intranasally administered, it decreased virus titers in the bronchoalveolar lavage fluid and the lung of mice infected with influenza A virus and increased survival rate. Furthermore, APS increased TNF-alpha and IFN-gamma levels in mice when compared with those of untreated mice. APS enhanced nitric oxide (NO) production and induced iNOS mRNA and protein expressions in RAW 264.7 murine macrophage cells. The induction of mRNA expression of cytokines including IL-1beta, IL-6, IL-10, and TNF-alpha was also observed. These results demonstrated that APS might have beneficial therapeutic effects on influenza A virus infection at least in part by modulation of the immune function of macrophages. PMID:17988090

Ohta, Yuko; Lee, Jung-Bum; Hayashi, Kyoko; Fujita, Akio; Park, Dong Ki; Hayashi, Toshimitsu

2007-12-12

226

Active players in resolution of shock/sepsis induced indirect lung injury: immunomodulatory effects of Tregs and PD-1.  

PubMed

The immunomodulatory effects of PD-1 and CD4(+)CD25(+) Tregs in the resolution of ALI are still poorly understood. Accordingly, 1 million Tregs were isolated from spleens of WT C57BL/6 or PD-1(-/-) mice (magnetical bead purification and subsequent labeling with/without Vybrant dye) and then AT into mice subjected to Hem shock during their resuscitation period, which were subsequently subjected to CLP/septic challenge (24 h post-Hem) to induce iALI. Initially, we demonstrated that Vybrant-labeled AT Tregs appear in the lungs of iALI mice. Subsequently, we found that AT of WT Tregs induced a significant repression of the indices of lung injury: a reduction of neutrophil influx to the lung tissue and a decrease of lung apoptosis compared with vehicle-treated iALI mice. In addition, these mice had substantially higher concentrations of BALF and lung-tissue IL-10 but significantly decreased levels of lung KC. However, these beneficial effects of the AT of Tregs were lost with the administration of PD-1(-/-) mouse Tregs to the recipient WT mice. ALI was exacerbated in these recipient mice receiving AT PD-1(-/-) Tregs to the same extent as iALI mice that did not receive Tregs. These data imply that Tregs can act directly to modify the innate immune response induced by experimental iALI, and this is mediated, in part, by PD-1. Hence, the manipulation of Tregs may represent a plausible target for treating iALI. PMID:25082151

Tang, Lunxian; Bai, Jianwen; Chung, Chun-Shiang; Lomas-Neira, Joanne; Chen, Yaping; Huang, Xin; Ayala, Alfred

2014-11-01

227

Immunomodulatory effects of Pteridium aquilinum on natural killer cell activity and select aspects of the cellular immune response of mice.  

PubMed

Pteridium aquilinum (bracken fern) is one of the most common plants. Epidemiological studies have revealed a higher risk of certain types of cancers (i.e., esophageal, gastric) in people who consume bracken fern directly (as crosiers or rhizomes) or indirectly through the consumption of milk from livestock that fed on the plant. In animals, evidence exists regarding the associations between chronic bracken fern intoxication, papilloma virus infection, and the development of carcinomas. While it is possible that some carcinogens in bracken fern could be responsible for these cancers in both humans and animals, it is equally plausible that the observed increases in cancers could be related to induction of an overall immunosuppression by the plant/its various constituents. Under the latter scenario, normal tumor surveillance responses against nascent (non-bracken-induced) cancers or responses against viral infections (specifically those linked to induction of cancers) might be adversely impacted by continuous dietary exposure to this plant. Therefore, the overall objective of this study was to evaluate the immunomodulatory effects of bracken fern following daily ingestion of its extract by a murine host over a period of 14 (or up to 30) days. In C57BL/6 mice administered (by gavage) the extract, histological analyses revealed a significant reduction in splenic white pulp area. Among a variety of immune response parameters/functions assessed in these hosts and isolated cells, both delayed-type hypersensitivity (DTH) analysis and evaluation of IFNgamma production by NK cells during T(H)1 priming were also reduced. Lastly, the innate response in these hosts-assessed by analysis of NK cell cytotoxic functionality-was also diminished. The results here clearly showed the immunosuppressive effects of P. aquilinum and that many of the functions that were modulated could contribute to the increased risk of cancer formation in exposed hosts. PMID:19589097

Latorre, Andréia Oliveira; Furlan, Maria Stella; Sakai, Mônica; Fukumasu, Heidge; Hueza, Isis Machado; Haraguchi, Mitsue; Górniak, Silvana Lima

2009-06-01

228

The activation of the arginine-citrulline cycle in macrophages from the spontaneously diabetic BB rat.  

PubMed Central

The activity of the arginine-citrulline cycle was investigated in macrophages from the spontaneous immunologically mediated diabetic BB rat. Peritoneal macrophages were prepared from male diabetes-prone (BBdp), diabetic (BBd) and age-matched non-diabetes-prone (BBn) rats. Cells were incubated at 37 degrees C for 2 h in Krebs-Henseleit bicarbonate buffer containing 0.5 mM L-arginine, 0.1 mM L-[ureido-14C]citrulline and 5 mM D-glucose to measure the activity of the arginine-citrulline cycle. The uptakes of citrulline and arginine by macrophages were measured during a 5 min incubation period with L-[ureido-14C]citrulline and L-[2,3-3H] arginine respectively. The production of NO3- (the major stable oxidation product of NO) increased (P < 0.01) by 112% and 151% in 75-day-old BBdp and 115-day-old BBd macrophages respectively, compared with age-matched BBn cells. The conversion of [14C]citrulline into [14C]arginine increased (P < 0.01) by 704%, 892% and 904% in 50- and 75-day-old BBdp and 115-day-old BBd macrophages respectively, compared with age-matched BBn cells. The enhanced NO synthesis in BBdp and BBd macrophages was associated with a 25-35% increase in the uptake of L-arginine. However, there were no differences in the uptake of citrulline between BBdp or BBd macrophages and age-matched BBn cells. Our results demonstrate for the first time the activation of the arginine-citrulline cycle in macrophages in an autoimmune condition. The inherent increase in the recycling of L-citrulline to L-arginine in BBdp and BBd macrophages may reflect an innate metabolic disorder in these cells. This increased L-arginine synthesis from L-citrulline may play a role in sustaining a sufficient intracellular L-arginine concentration for prolonged generation of NO in BBdp and BBd macrophages. A role for NO in the autoimmune destruction of pancreatic beta-cells in insulin-dependent diabetes mellitus warrants further investigation. PMID:8363561

Wu, G; Flynn, N E

1993-01-01

229

CD14 influences host immune responses and alternative activation of macrophages during Schistosoma mansoni infection.  

PubMed

Antigen-presenting cell (APC) plasticity is critical for controlling inflammation in metabolic diseases and infections. The roles that pattern recognition receptors (PRRs) play in regulating APC phenotypes are just now being defined. We evaluated the expression of PRRs on APCs in mice infected with the helminth parasite Schistosoma mansoni and observed an upregulation of CD14 expression on macrophages. Schistosome-infected Cd14(-/-) mice showed significantly increased alternative activation of (M2) macrophages in the livers compared to infected wild-type (wt) mice. In addition, splenocytes from infected Cd14(-/-) mice exhibited increased production of CD4(+)-specific interleukin-4 (IL-4), IL-5, and IL-13 and CD4(+)Foxp3(+)IL-10(+) regulatory T cells compared to cells from infected wt mice. S. mansoni-infected Cd14(-/-) mice also presented with smaller liver egg granulomas associated with increased collagen deposition compared to granulomas in infected wt mice. The highest expression of CD14 was found on liver macrophages in infected mice. To determine if the Cd14(-/-) phenotype was in part due to increased M2 macrophages, we adoptively transferred wt macrophages into Cd14(-/-) mice and normalized the M2 and CD4(+) Th cell balance close to that observed in infected wt mice. Finally, we demonstrated that CD14 regulates STAT6 activation, as Cd14(-/-) mice had increased STAT6 activation in vivo, suggesting that lack of CD14 impacts the IL-4R?-STAT6 pathway, altering macrophage polarization during parasite infection. Collectively, these data identify a previously unrecognized role for CD14 in regulating macrophage plasticity and CD4(+) T cell biasing during helminth infection. PMID:24866794

Tundup, Smanla; Srivastava, Leena; Nagy, Tamas; Harn, Donald

2014-08-01

230

INTERLEUKIN-4- AND INTERLEUKIN-13-MEDIATED ALTERNATIVELY ACTIVATED MACROPHAGES: ROLES IN HOMEOSTASIS AND DISEASE  

PubMed Central

The macrophage, a versatile cell type prominently involved in host defense and immunity, assumes a distinct state of alternative activation in the context of polarized type 2 immune responses such as allergic inflammation and helminth infection. This alternatively activated phenotype is induced by the canonical type 2 cytokines interleukin (IL)-4 and IL-13, which mediate expression of several characteristic markers along with a dramatic shift in macrophage metabolic pathways that influence surrounding cells and tissues. We discuss recent advances in the understanding of IL-4- and IL-13-mediated alternatively activated macrophages and type 2 immune responses; such advances have led to an expanded appreciation for functions of these cells beyond immunity, including maintenance of physiologic homeostasis and tissue repair. PMID:23298208

Van Dyken, Steven J.; Locksley, Richard M.

2013-01-01

231

Induction of Rapid T Cell Death and Phagocytic Activity by Fas-Deficient lpr Macrophages  

PubMed Central

Peripheral T cells are maintained by the apoptosis of activated T cells through the Fas–Fas ligand system. Although it is well known that normal T cells fail to survive in the Fas-deficient immune condition, the molecular mechanism for the phenomenon has yet to be elucidated. In this study, we demonstrate that rapid cell death and clearance of normal T cells were induced by Fas-deficient lpr macrophages. Transfer of normal T cells into lpr mice revealed that Fas expression on donor T cells was promptly enhanced through the IFN-?/IFN-?R. In addition, Fas ligand expression and phagocytic activity of lpr macrophages were promoted through increased NF-?B activation. Controlling Fas expression on macrophages plays an essential role in maintaining T cell homeostasis in the peripheral immune system. Our data suggest a critical implication to the therapeutic strategies such as transplantation and immunotherapy for immune disorder or autoimmunity related to abnormal Fas expression. PMID:23255359

Oura, Ritsuko; Arakaki, Rieko; Yamada, Akiko; Kudo, Yasusei; Tanaka, Eiji; Hayashi, Yoshio

2013-01-01

232

Immunomodulatory Effect of Mangiferin in Experimental Animals with Benzo(a)Pyrene-induced Lung Carcinogenesis.  

PubMed

The immunomodulatory activity of mangiferin was studied in various groups of animals. For this study, adult Swiss albino male mice were treated with benzo(a)pyrene, abbreviated as B(a)P, at 50 mg/kg body weight orally twice a week for 4 weeks; and mangiferin was also given orally (pre- and post-initiation of carcinoma) at 100 mg/kg body weight. Immunocompetence and immune complexes as measured by phagocyte index, avidity index, and soluble immune complex (SIC) levels (p<0.001), as well as NBT reduction, were decreased in the B(a)P-treated animals;whereas increased levels of immunocompetence were noted in the mangiferin-treated animals given B(a)P (p<0.001, p<0.05). The levels of immunoglobulins such as IgG and IgM were decreased considerably (p<0.001) in the B(a)P-treated animals compared with their levels in the control animals; whereas the IgA level was increased (p<0.001). In the mangiferin-treated experimental animals given B(a)P, the levels of IgG and IgM were significantly (p<0.001, p<0.05) increased whereas the IgA level was decreased compared with those for the B(a)P-treated mice. Oxidative changes in lymphocytes, neutrophils, and macrophages were also measured. The enhanced lipid peroxidation and decreased catalase and superoxide dismutase activities found in the lymphocytes, polymorphonuclear cells (PMN), and macrophages from B(a)P-treated mice were significantly reduced and increased, respectively, by the mangiferin treatment. This study confirms the immunomodulatory effect of mangiferin and shows an immunoprotective role arbitrated through a reduction in the reactive intermediate-induced oxidative stress in lymphocytes, neutrophils, and macrophages. PMID:23847456

Rajendran, Peramaiyan; Jayakumar, Thangavel; Nishigaki, Ikuo; Ekambaram, Ganapathy; Nishigaki, Yutaka; Vetriselvi, Jayabal; Sakthisekaran, Dhanapal

2013-06-01

233

Immunomodulatory Effect of Mangiferin in Experimental Animals with Benzo(a)Pyrene-induced Lung Carcinogenesis  

PubMed Central

The immunomodulatory activity of mangiferin was studied in various groups of animals. For this study, adult Swiss albino male mice were treated with benzo(a)pyrene, abbreviated as B(a)P, at 50 mg/kg body weight orally twice a week for 4 weeks; and mangiferin was also given orally (pre- and post-initiation of carcinoma) at 100 mg/kg body weight. Immunocompetence and immune complexes as measured by phagocyte index, avidity index, and soluble immune complex (SIC) levels (p<0.001), as well as NBT reduction, were decreased in the B(a)P-treated animals;whereas increased levels of immunocompetence were noted in the mangiferin-treated animals given B(a)P (p<0.001, p<0.05). The levels of immunoglobulins such as IgG and IgM were decreased considerably (p<0.001) in the B(a)P-treated animals compared with their levels in the control animals; whereas the IgA level was increased (p<0.001). In the mangiferin-treated experimental animals given B(a)P, the levels of IgG and IgM were significantly (p<0.001, p<0.05) increased whereas the IgA level was decreased compared with those for the B(a)P-treated mice. Oxidative changes in lymphocytes, neutrophils, and macrophages were also measured. The enhanced lipid peroxidation and decreased catalase and superoxide dismutase activities found in the lymphocytes, polymorphonuclear cells (PMN), and macrophages from B(a)P-treated mice were significantly reduced and increased, respectively, by the mangiferin treatment. This study confirms the immunomodulatory effect of mangiferin and shows an immunoprotective role arbitrated through a reduction in the reactive intermediate-induced oxidative stress in lymphocytes, neutrophils, and macrophages. PMID:23847456

Rajendran, Peramaiyan; Jayakumar, Thangavel; Nishigaki, Ikuo; Ekambaram, Ganapathy; Nishigaki, Yutaka; Vetriselvi, Jayabal; Sakthisekaran, Dhanapal

2013-01-01

234

Folic acid-functionalized human serum albumin nanocapsules for targeted drug delivery to chronically activated macrophages.  

PubMed

Activated synovial macrophages play a key role in Rheumatoid Arthritis (RA). Recent studies have shown that folate receptor beta (FR?) is specifically expressed by activated macrophages. Therefore a folate-based nanodevice would provide the possibility of delivering therapeutic agents to activated macrophages without affecting normal cells and tissues. This study shows for the first time the sonochemical preparation of HSA nanocapsules avoiding toxic cross linking chemicals and emulsifiers used in other methods. Production of HSA nanocapsules was optimized leading to a diameter of 443.5 ± 9.0 nm and a narrow size distribution indicated by a polydispersity index (PDI) of 0.066 ± 0.080. Nanocapsules were surface modified with folic acid (FA) and the FA content was determined to be 0.38 and 6.42 molecules FA per molecule HSA, depending on the surplus of FA employed. Dynamic light scattering was used to determine size, PDI and zetapotential of the produced nanocapsules before and after surface modification. FA distribution on the surface of HSA nanocapsules was localized three-dimensionally after fluorescence labeling using confocal laser scanning microscopy (CLSM). Furthermore, specific binding and internalization of HSA nanocapsules by FR?-positive and FR?-negative macrophages, obtained from human peripheral blood mononuclear cells, was demonstrated by flow cytometry. FR?-expressing macrophages showed an increased binding for FA-modified capsules compared with those without FA. PMID:22374516

Rollett, Alexandra; Reiter, Tamara; Nogueira, Patricia; Cardinale, Massimiliano; Loureiro, Ana; Gomes, Andreia; Cavaco-Paulo, Artur; Moreira, Alexandra; Carmo, Alexandre M; Guebitz, Georg M

2012-05-10

235

Macrophage stimulating protein: purification, partial amino acid sequence, and cellular activity  

PubMed Central

Macrophage stimulating protein (MSP) was purified to homogeneity from human blood plasma by selection of biologically active fractions obtained by sequential immunoaffinity and high pressure liquid ion exchange chromatography. By sodium dodecyl sulfate-polyacrylamide gel electrophoresis the molecular mass of MSP was 70 kilodaltons (kD); under reducing conditions two gel bands were seen, at 47 and 22 kD. The disulfide-linked two-chain structure of MSP was confirmed by separation of reduced and alkylated MSP chains. A computer search comparison of six partial sequences of MSP digests showed that MSP has not been recorded in data banks of protein sequences. Two MSP fragments had greater than 80% identity in overlaps of 12-16 residues to sequences in the protein family that includes human prothrombin, plasminogen, and hepatocyte growth factor. The concentration of purified MSP required for half-maximal biological activity was the order of 10(-10) M. In addition to making mouse resident peritoneal macrophages responses to chemoattractants, MSP caused the appearance of long cytoplasmic processes and pinocytic vesicles in freshly plated macrophages. MSP also caused phagocytosis via the C3b receptor, CR1. Whereas resident peritoneal macrophages bind but do not ingest sheep erythrocytes opsonized with IgM anti-Forssman antibody and mouse C3b, addition of MSP caused ingestion. Thus, MSP causes direct or indirect activation of two receptors of the mouse resident peritoneal macrophage, CR1 and the C5a receptor. PMID:1827141

1991-01-01

236

Gene Deficiency in Activating Fc? Receptors Influences the Macrophage Phenotypic Balance and Reduces Atherosclerosis in Mice  

PubMed Central

Immunity contributes to arterial inflammation during atherosclerosis. Oxidized low-density lipoproteins induce an autoimmune response characterized by specific antibodies and immune complexes in atherosclerotic patients. We hypothesize that specific Fc? receptors for IgG constant region participate in atherogenesis by regulating the inflammatory state of lesional macrophages. In vivo we examined the role of activating Fc? receptors in atherosclerosis progression using bone marrow transplantation from mice deficient in ?-chain (the common signaling subunit of activating Fc? receptors) to hyperlipidemic mice. Hematopoietic deficiency of Fc? receptors significantly reduced atherosclerotic lesion size, which was associated with decreased number of macrophages and T lymphocytes, and increased T regulatory cell function. Lesions of Fc? receptor deficient mice exhibited increased plaque stability, as evidenced by higher collagen and smooth muscle cell content and decreased apoptosis. These effects were independent of changes in serum lipids and antibody response to oxidized low-density lipoproteins. Activating Fc? receptor deficiency reduced pro-inflammatory gene expression, nuclear factor-?B activity, and M1 macrophages at the lesion site, while increasing anti-inflammatory genes and M2 macrophages. The decreased inflammation in the lesions was mirrored by a reduced number of classical inflammatory monocytes in blood. In vitro, lack of activating Fc? receptors attenuated foam cell formation, oxidative stress and pro-inflammatory gene expression, and increased M2-associated genes in murine macrophages. Our study demonstrates that activating Fc? receptors influence the macrophage phenotypic balance in the artery wall of atherosclerotic mice and suggests that modulation of Fc? receptor-mediated inflammatory responses could effectively suppress atherosclerosis. PMID:23805273

Mallavia, Benat; Oguiza, Ainhoa; Lopez-Franco, Oscar; Recio, Carlota; Ortiz-Munoz, Guadalupe; Lazaro, Iolanda; Lopez-Parra, Virginia; Egido, Jesus; Gomez-Guerrero, Carmen

2013-01-01

237

Lung Collagens Perpetuate Pulmonary Fibrosis via CD204 and M2 Macrophage Activation  

PubMed Central

Idiopathic pulmonary fibrosis is characterized by abundant collagen production and accumulation of alternatively activated macrophages (M2) in the lower respiratory tract. Mechanisms as to how alveolar macrophages are activated by collagen breakdown products are unknown. Alveolar macrophages were obtained by bronchoalveolar lavage from 30 patients with idiopathic pulmonary fibrosis (IPF) and 37 healthy donors (HD). Alveolar macrophages were cultured in the presence of collagen type I, III, IV and V monomers w/wo a neutralizing antibody against scavenger receptor I class A (CD204). Culture supernatants were assayed for the M2 markers CCL18, CCL2, and interleukin-1 receptor antagonist (IL-1ra) by ELISA. Furthermore, expression of phospho-Akt was measured using ELISA and expression of CD204 by RT-PCR and flow cytometry. Stimulation with collagen type I and III monomers significantly up-regulated CCL18, IL-1ra production of alveolar macrophages. Furthermore, expression of CCL2 and CD204 were up-regulated by collagen type I exposure. In addition, collagen type I stimulation increased pospho-Akt expression. Collagen type I effects were abrogated by neutralizing antiCD204 and a non-selective Phosphatidylinositide 3-kinase inhibitor (LY294002). Spontaneous CD204 expression of alveolar macrophages was significantly increased in patients with IPF. In conclusion, our findings demonstrate that monomeric collagen type I via CD204 induces phospho-Akt expression shifting alveolar macrophages to the profibrotic M2 type. Innate immune responses induced by collagen monomers might perpetuate pulmonary fibrosis. PMID:24278429

Stahl, Mirjam; Schupp, Jonas; Jager, Benedikt; Schmid, Michael; Zissel, Gernot; Muller-Quernheim, Joachim; Prasse, Antje

2013-01-01

238

Lung collagens perpetuate pulmonary fibrosis via CD204 and M2 macrophage activation.  

PubMed

Idiopathic pulmonary fibrosis is characterized by abundant collagen production and accumulation of alternatively activated macrophages (M2) in the lower respiratory tract. Mechanisms as to how alveolar macrophages are activated by collagen breakdown products are unknown. Alveolar macrophages were obtained by bronchoalveolar lavage from 30 patients with idiopathic pulmonary fibrosis (IPF) and 37 healthy donors (HD). Alveolar macrophages were cultured in the presence of collagen type I, III, IV and V monomers w/wo a neutralizing antibody against scavenger receptor I class A (CD204). Culture supernatants were assayed for the M2 markers CCL18, CCL2, and interleukin-1 receptor antagonist (IL-1ra) by ELISA. Furthermore, expression of phospho-Akt was measured using ELISA and expression of CD204 by RT-PCR and flow cytometry. Stimulation with collagen type I and III monomers significantly up-regulated CCL18, IL-1ra production of alveolar macrophages. Furthermore, expression of CCL2 and CD204 were up-regulated by collagen type I exposure. In addition, collagen type I stimulation increased pospho-Akt expression. Collagen type I effects were abrogated by neutralizing antiCD204 and a non-selective Phosphatidylinositide 3-kinase inhibitor (LY294002). Spontaneous CD204 expression of alveolar macrophages was significantly increased in patients with IPF. In conclusion, our findings demonstrate that monomeric collagen type I via CD204 induces phospho-Akt expression shifting alveolar macrophages to the profibrotic M2 type. Innate immune responses induced by collagen monomers might perpetuate pulmonary fibrosis. PMID:24278429

Stahl, Mirjam; Schupp, Jonas; Jäger, Benedikt; Schmid, Michael; Zissel, Gernot; Müller-Quernheim, Joachim; Prasse, Antje

2013-01-01

239

Mesenchymal stem cells ameliorate rhabdomyolysis-induced acute kidney injury via the activation of M2 macrophages  

PubMed Central

Introduction The mortality of rhabdomyolysis-induced acute kidney injury (AKI) is still high, as there is no effective therapy. It has been shown that bone marrow-derived mesenchymal stem cells (MSCs) can induce M2 macrophages, which mediate MSC protection in other experimental inflammation-related organ injury. This study was designed to investigate the protective effects of macrophage activation in MSC therapy of rhabdomyolysis-induced AKI. Methods MSCs were injected into glycerol-induced rhabdomyolysis mice. Renal injury was evaluated using the serum creatinine, urea nitrogen, renal pathology and acute tubular necrosis score. The distribution of MSCs was detected using two-photon fluorescence confocal imaging. Immunofluorescence of anti-F4/80 and anti-CD206 was performed to determine macrophages and M2 macrophages in the tissues of the kidney, and M2 macrophage infiltration was also evaluated using western blotting analyses. After depletion of macrophages using clodronate liposomes at the phase of kidney repair, renal injury was re-evaluated. RAW 264.7 macrophages were incubated with lipopolysaccharide and co-cultured with MSCs and subsequently visualised using immunofluorescence staining and flow cytometry analysis. Finally, disparate phenotype macrophages, including normal macrophages (M0), lipopolysaccharide-stimulated macrophages (M1), and MSC-co-cultured macrophages (M2), were infused into mice with AKI, which were pre-treated with liposomal clodronate. Results In vivo infusion of MSCs protected AKI mice from renal function impairment and severe tubular injury, which was accompanied by a time-dependent increase in CD206-positive M2 macrophage infiltration. In addition, depleting macrophages with clodronate delayed restoration of AKI. In vitro, macrophages co-cultured with MSCs acquired an anti-inflammatory M2 phenotype, which was characterised by an increased expression of CD206 and the secretory cytokine interleukin (IL)-10. The concentrations of IL-10, IL-6 and tumor necrosis factor ? were evaluated using enzyme-linked immunosorbent assay. Furthermore, macrophage-depleted mice with intramuscular injection of glycerol were subjected to a single injection of different types of RAW 264.7 macrophages. Mice infused with M0 and M1 macrophages suffered a more severe histological and functional injury, while mice transfused with MSC-educated M2 macrophages showed reduced kidney injury. Conclusions Our findings suggested that MSCs can ameliorate rhabdomyolysis-induced AKI via the activation of macrophages to a trophic M2 phenotype, which supports the transition from tubule injury to tubule repair. PMID:24961539

2014-01-01

240

Extracellular cytolysis by activated macrophages and granulocytes. II. Hydrogen peroxide as a mediator of cytotoxicity  

PubMed Central

When deprived of oxygen, Bacille Calmette-Guerin (BCG)-activated macrophages no longer lysed P388 lymphoma cells. Both H2O2 release and cytotoxicity by BCG-activated macrophages and by granulocytes triggered with phorbol myristate acetate (PMA) were markedly inhibited when the glucose concentration in the medium was reduced to 0.03 mM or less, or if glucose were replaced with galactose. Catalase abolished PMA- triggered cytotoxicity by both types of effector cells, whereas superoxide dismutase had no effect. Ferricytochrome C reduced the cytotoxicity of BCG-activated macrophages, an effect which was largely reversed by superoxide dismutase. 10 drugs, thought to quench singlet oxygen and/or scavenge hydroxyl radical, did not affect cytotoxicity in this system. Neither azide nor cyanide reduced cytolysis, but there was marked inhibition by lactoperoxidase and iodide. This suggested that cytotoxicity was not dependent upon myeloperoxidase, and that lactoperoxidase may have diverted H2O2 from the oxidation of target cells to oxidation of substances in serum. Mouse erythrocytes, although sensitive targets, interfered with the cytolysis of lymphoma cells, probably by competition for H2O2. Starch particles with covalently bound glucose oxidase resembled macrophages in their spatial relation to the target cells and in the flux of H2O2 they generated from their surface, but were not expected to produce any other potentially toxic products. Such particles lysed lymphoma cells, and the lysis was prevented by catalase. Neither arginase nor thymidine appeared to be involved in cytolysis by BCG-activated macrophages under the conditions used. These findings demonstrated that release of H2O2 was both necessary and sufficient for cytolysis by BCG-activated macrophages and by granulocytes when pharmacologically triggered. PMID:216763

1979-01-01

241

Direct activation of the J774.1 Murine macrophage cell line by mycoplasma arthritidis.  

PubMed Central

Viable Mycoplasma arthritidis and supernatants from M. arthriditis cultures produced marked morphological changes in the J774.1 continuous macrophage line similar to those seen during activation of these cells by Mycobacterium bovis BCG cell walls. The mycoplasma-treated macrophages developed pronounced tumoricidal activity against syngenic 3T12-3 target cells and developed an enhanced capacity for the killing of intracellular listeriae, including both virulent and laboratory-maintained strains. Increased acid phosphatase levels and [14C]glucosamine uptake were also seen. We conclude that mycoplasmas can profoundly alter the functions of macrophages, an event which may not only have in vivo significance with regard to disease pathogenesis, but which may pose considerable problems for in vitro work when unsuspected mycoplasma contamination is present. Images PMID:6811441

Dietz, J N; Cole, B C

1982-01-01

242

Rat Macrophage C-Type Lectin Is an Activating Receptor Expressed by Phagocytic Cells  

PubMed Central

Macrophage C-type lectin (MCL) is a membrane surface receptor encoded by the Antigen Presenting Lectin-like gene Complex (APLEC). We generated a mouse monoclonal antibody for the study of this receptor in the rat. We demonstrate that rat MCL is expressed on blood monocytes and neutrophils, as well as on several tissue macrophage populations, including alveolar and peritoneal cavity macrophages. We also demonstrate MCL expression on a subset of resident spleen macrophages. Immunohistochemistry analysis of the spleen showed staining specifically in the marginal zone and red pulp. Exposure to pro-inflammatory mediators or to yeast cell wall extract (zymosan) increased surface MCL expression on peritoneal macrophages. We characterized a rat myeloid cell line, RMW, which expresses high levels of MCL. We found that MCL co-immunoprecipitated with the activating adaptor protein Fc?RI? in these cells. Moreover, beads coated with anti-MCL antibody increased phagocytosis in the RMW cells. Together, these observations indicate that rat MCL is a receptor that activates phagocytosis in myeloid cells under inflammatory conditions. PMID:23468983

Lobato-Pascual, Ana; Saether, Per Christian; Dahle, Maria K.; Gaustad, Peter; Dissen, Erik; Fossum, Sigbj?rn; Daws, Michael R.

2013-01-01

243

Classically or alternatively activated bovine monocyte-derived macrophages in vitro do not resemble CD163/Calprotectin biased macrophage populations in the teat.  

PubMed

The functional phenotype of resident macrophages significantly determines the character of an inflammatory response. In this study we identified two phenotypes of tissue macrophages in bovine teat tissue based on expression of Calprotectin and CD163. To investigate a possible link between the dichotomy in phenotype and functional properties of cells in association with different host mediators we set up an in vitro model with bovine monocyte-derived macrophages (MdM). In vitro differentiated MdM invariably and uniformly expressed both antigens. Classically activated MdM (IFN-? priming and LPS stimulation) showed a decreased CD163 expression while alternative activation (IL-4/IL-13 priming) did not change expression of CD163 and Calprotectin. Differently activated MdM showed a clearly distinct expression of genes related to classical (IL-12, inducible NO synthase) or alternative activation (IL-10, arginase I). The presence of the inflammatory host mediator prostaglandin E(2) (PGE(2)) neither influenced expression of Calprotectin and CD163 nor gene expression profiles in MdM generated in the presence of PGE(2) (PGE(2)-MdM). Supernatants of PGE(2-)MdM, however, significantly dampened the migration of neutrophilic granulocytes. The results of this study highlight the discrepancy between in vivo and in vitro obtained macrophages and point to the necessity to analyze the functional capacities of bovine tissue macrophages in situ. PMID:22627785

Düvel, Anna; Frank, Constanze; Schnapper, Anke; Schuberth, Hans-Joachim; Sipka, Anja

2012-12-01

244

Identification of cyclophilin as a proinflammatory secretory product of lipopolysaccharide-activated macrophages.  

PubMed Central

We have isolated an 18-kDa peptide (designated sp18, for 18-kDa secreted protein) from the conditioned medium of lipopolysaccharide-stimulated RAW 264.7 murine macrophages. Purified sp18 had in vivo inflammatory activity and in vitro chemotactic activity for human peripheral blood polymorphonuclear leukocytes and monocytes. Surprisingly, N-terminal sequencing and tryptic mapping studies revealed that sp18 and cyclophilin, an intracellular protein that binds the immunosuppressive drug cyclosporin A, are highly homologous. The in vitro chemotactic activity of sp18 on monocytes was blocked by cyclosporin A but not by cyclosporin H, a structural analog of cyclosporin A that does not bind cyclophilin. Like purified porcine cyclophilin, mouse sp18 exhibited peptidyl-prolyl cis-trans isomerase activity. Medium conditioned by lipopolysaccharide-stimulated resident peritoneal exudate macrophages isolated from C57BL/6 mice contained substantially higher levels of sp18/cyclophilin than medium conditioned by nonstimulated macrophages. The observation that sp18/cyclophilin exhibits proinflammatory activity and is secreted by macrophages in response to endotoxin suggests that this protein may function as a cytokine, and invites the hypothesis that the immunosuppressive action of cyclosporin A results in part from interaction with an extracellular form of cyclophilin released as a mediator of immune and inflammatory functions. Images PMID:1565646

Sherry, B; Yarlett, N; Strupp, A; Cerami, A

1992-01-01

245

Complement activation by the alternative pathway and macrophage enzyme secretion in the pathogenesis of chronic inflammation.  

PubMed Central

A number of stimuli known to induce acid hydrolase secretion from cultured macrophages were examined for their ability to activate C3 via the alternative pathway of the complement system. Loss of haemolytically active C3 was checked in normal and C4-deficient guinea-pig serum. For comparison the interactions of cultured macrophages with other agents well known as potent activators of the alternative pathway of the complement system have been investigated. As judged by their activity in these assays, group A streptococcal cell walls, different carrageenan preparations, dental plaque and Actinomyces viscosus were all capable of initiating the alternative pathway but differed with respect to their potency and their ability to inhibit C3 turnover at high concentrations. Zymosan, some carrageenans, polyanethol sulphonate, and Corynebacterium parvum all induce the release of hydrolytic enzymes from macrophages in culture, even in the absence of serum in the medium. The release is time- and dose-dependent and is not associated with loss of the cytoplasmic enzyme lactate dehydrogenase or any other sign of cell death. The parallelism between the capacity of several agents to activate the complement system via the alternative pathway and to induce inflammatory responses in vivo and selective lysosoma enzyme secretion from cultures of macrophages is discussed. PMID:328387

Schorlemmer, H U; Bitter-Suermann, D; Allison, A C

1977-01-01

246

Extracellular polysaccharides produced by Ganoderma formosanum stimulate macrophage activation via multiple pattern-recognition receptors  

PubMed Central

Background The fungus of Ganoderma is a traditional medicine in Asia with a variety of pharmacological functions including anti-cancer activities. We have purified an extracellular heteropolysaccharide fraction, PS-F2, from the submerged mycelia culture of G. formosanum and shown that PS-F2 exhibits immunostimulatory activities. In this study, we investigated the molecular mechanisms of immunostimulation by PS-F2. Results PS-F2-stimulated TNF-? production in macrophages was significantly reduced in the presence of blocking antibodies for Dectin-1 and complement receptor 3 (CR3), laminarin, or piceatannol (a spleen tyrosine kinase inhibitor), suggesting that PS-F2 recognition by macrophages is mediated by Dectin-1 and CR3 receptors. In addition, the stimulatory effect of PS-F2 was attenuated in the bone marrow-derived macrophages from C3H/HeJ mice which lack functional Toll-like receptor 4 (TLR4). PS-F2 stimulation triggered the phosphorylation of mitogen-activated protein kinases JNK, p38, and ERK, as well as the nuclear translocation of NF-?B, which all played essential roles in activating TNF-? expression. Conclusions Our results indicate that the extracellular polysaccharides produced by G. formosanum stimulate macrophages via the engagement of multiple pattern-recognition receptors including Dectin-1, CR3 and TLR4, resulting in the activation of Syk, JNK, p38, ERK, and NK-?B and the production of TNF-?. PMID:22883599

2012-01-01

247

Screening for immunomodulators: Effects of xenobiotics on macrophage chemiluminescence in vitro  

SciTech Connect

Macrophage chemiluminescence (CL) was evaluated as a primary screening assay by assessing the modulatory activity of 17 different chemicals. The chemicals were either known immunomodulatory drugs or environmental toxicants with reported immunomodulatory activity. Elicited mouse peritoneal macrophages were exposed to the chemicals in vitro, and CL was measured in response to an opsonized yeast stimulus. Ten chemicals (hydrocortisone, dextran sulfate, di-n-octyltin dichloride, dimethyltin dichloride, azathioprine, lambda carrageenan (l-carrageenan), lead, N-propyl gallate, gallic acid, and indomethacin) were identified as effective modulators of CL. The polyanions dextran sulfate and l-carrageenan either suppressed or enhanced CL, depending on the experimental conditions, while the remaining modulators were inhibitory. A series of secondary assays was used to verify this modulatory activity and to explore different mechanisms of action. Each effective modulator altered only a few specific components of the more complex CL response, and the following general mechanisms were apparent. At least 2 chemicals showed distinct antioxidant activity and thus probably did not alter functional aspects of macrophage CL. Chemicals which blocked Fc receptor function delayed the peak CL of macrophages stimulated by opsonized yeast. Nine of the 10 modulators inhibited hydrogen peroxide release, but only 3 inhibited the release of superoxide. Finally, some effective modulators were chemicals known to interact with cell membranes or specific membrane receptors, and these were able to directly induce a CL response without the addition of opsonized yeast as a stimulus. Thus, macrophage CL was a simple, quantitative, yet sensitive immunotoxicologic screening assay capable of identifying many known immunomodulatory drugs.

Tam, P.E.; Hinsdill, R.D. (Univ. of Wisconsin, Madison (USA))

1990-04-01

248

Class A scavenger receptor activation inhibits endoplasmic reticulum stress-induced autophagy in macrophage  

PubMed Central

Abstract Macrophage death in advanced atherosclerosis promotes plaque necrosis and destabilization. Involvement of autophagy in bulk degradation of cellular components has been recognized recently as an important mechanism for cell survival under endoplasmic reticulum (ER) stress. We previously found that the engagement of class A scavenger receptor (SR-A) triggered JNK-dependent apoptosis in ER-stressed macrophages. However, pro-apoptotic mechanisms mediated by SR-A are not fully understood. Therefore, we sought to see if SR-A mediated apoptosis was associated with autophagy in macrophages. Here, we showed that fucoidan inhibited microtubule-associated protein light chain 3-phospholipid conjugates (LC3-II) formation as well as the number of autophagosomes under ER stress. The inhibition of LC3-II formation was paralleled by the activation of the mTOR pathway, and the inhibition of mTOR allowed LC3-II induction in macrophages treated with thapsigargin plus fucoidan. Furthermore, apoptosis induced by fucoidan was prevented under ER stress by the mTOR inhibitor. We propose that fucoidan, a SR-A agonist, may contribute to macrophage apoptosis during ER stress by inhibiting autophagy. PMID:25013404

Huang, Hanpeng; Li, Xiaoyu; Zhuang, Yan; Li, Nan; Zhu, Xudong; Hu, Jin; Ben, Jingjing; Yang, Qing; Bai, Hui; Chen, Qi

2014-01-01

249

Class A scavenger receptor activation inhibits endoplasmic reticulum stress-induced autophagy in macrophage.  

PubMed

Macrophage death in advanced atherosclerosis promotes plaque necrosis and destabilization. Involvement of autophagy in bulk degradation of cellular components has been recognized recently as an important mechanism for cell survival under endoplasmic reticulum (ER) stress. We previously found that the engagement of class A scavenger receptor (SR-A) triggered JNK-dependent apoptosis in ER-stressed macrophages. However, pro-apoptotic mechanisms mediated by SR-A are not fully understood. Therefore, we sought to see if SR-A mediated apoptosis was associated with autophagy in macrophages. Here, we showed that fucoidan inhibited microtubule-associated protein light chain 3-phospholipid conjugates (LC3-II) formation as well as the number of autophagosomes under ER stress. The inhibition of LC3-II formation was paralleled by the activation of the mTOR pathway, and the inhibition of mTOR allowed LC3-II induction in macrophages treated with thapsigargin plus fucoidan. Furthermore, apoptosis induced by fucoidan was prevented under ER stress by the mTOR inhibitor. We propose that fucoidan, a SR-A agonist, may contribute to macrophage apoptosis during ER stress by inhibiting autophagy. PMID:25013404

Huang, Hanpeng; Li, Xiaoyu; Zhuang, Yan; Li, Nan; Zhu, Xudong; Hu, Jin; Ben, Jingjing; Yang, Qing; Bai, Hui; Chen, Qi

2014-05-01

250

Macrophage activation state determines the response to rhinovirus infection in a mouse model of allergic asthma  

PubMed Central

Background The mechanisms by which viruses cause asthma exacerbations are not precisely known. Previously, we showed that, in ovalbumin (OVA)-sensitized and -challenged mice with allergic airway inflammation, rhinovirus (RV) infection increases type 2 cytokine production from alternatively-activated (M2) airway macrophages, enhancing eosinophilic inflammation and airways hyperresponsiveness. In this paper, we tested the hypothesis that IL-4 signaling determines the state of macrophage activation and pattern of RV-induced exacerbation in mice with allergic airways disease. Methods Eight week-old wild type or IL-4 receptor knockout (IL-4R KO) mice were sensitized and challenged with OVA and inoculated with RV1B or sham HeLa cell lysate. Results In contrast to OVA-treated wild-type mice with both neutrophilic and eosinophilic airway inflammation, OVA-treated IL-4R KO mice showed increased neutrophilic inflammation with few eosinophils in the airways. Like wild-type mice, IL-4R KO mice showed OVA-induced airway hyperreactivity which was further exacerbated by RV. There was a shift in lung cytokines from a type 2-predominant response to a type 1 response, including production of IL-12p40 and TNF-?. IL-17A was also increased. RV infection of OVA-treated IL-4R KO mice further increased neutrophilic inflammation. Bronchoalveolar macrophages showed an M1 polarization pattern and ex vivo RV infection increased macrophage production of TNF-?, IFN-? and IL-12p40. Finally, lung cells from OVA-treated IL-4R KO mice showed reduced CD206+ CD301+ M2 macrophages, decreased IL-13 and increased TNF-? and IL-17A production by F4/80+, CD11b+?macrophages. Conclusions OVA-treated IL-4R KO mice show neutrophilic airway inflammation constituting a model of allergic, type 1 cytokine-driven neutrophilic asthma. In the absence of IL-4/IL-13 signaling, RV infection of OVA-treated mice increased type 1 cytokine and IL-17A production from conventionally-activated macrophages, augmenting neutrophilic rather than eosinophilic inflammation. In mice with allergic airways inflammation, IL-4R signaling determines macrophage activation state and the response to subsequent RV infection. PMID:24907978

2014-01-01

251

Cytoprotective activity of Amla (Emblica officinalis) against chromium (VI) induced oxidative injury in murine macrophages.  

PubMed

The cytoprotective and immunomodulating properties of Emblica officinalis (Amla) against chromium (VI) induced oxidative damage are reported. Chromium (VI) at 1 micro g/mL concentration was highly cytotoxic. It enhanced free radical production and decreased reduced glutathione (GSH) levels and glutathione peroxidase (GPx) activity in macrophages. The presence of Amla resulted in an enhanced cell survival, decreased free radical production and higher antioxidant levels similar to that of control cells. Further, chromium (VI) treatment resulted in decreased phagocytosis and gamma-interferon (gamma-IFN) production while Amla inhibited chromium induced immunosuppression and restored both phagocytosis and gamma-IFN production by macrophages significantly. PMID:12722158

Sai Ram, M; Neetu, D; Deepti, P; Vandana, M; Ilavazhagan, G; Kumar, Devendra; Selvamurthy, W

2003-04-01

252

Alternate radiolabeled markers for detecting metabolic activity of Mycobacterium leprae residing in murine macrophages  

SciTech Connect

This study demonstrated the utility of using 4% NaOH as a murine macrophage cell-solubilizing agent to discriminate between host macrophage metabolism and that of intracellular Mycobacterium leprae. A 4% concentration of NaOH had no deleterious effect on labeled mycobacteria. Thereby, alternate radiolabeled indicators of the metabolic activity of intracellular M. leprae could be experimented with. Significant incorporation of /sup 14/C-amino acid mixture, (/sup 14/C)leucine, (/sup 14/C)uridine, and carrier-free /sup 32/P was observed in cultures containing freshly extracted (''live'') strains of M. leprae as compared with control cultures containing autoclaved bacilli.

Prasad, H.K.; Hastings, R.C.

1985-05-01

253

Functional Roles of p38 Mitogen-Activated Protein Kinase in Macrophage-Mediated Inflammatory Responses  

PubMed Central

Inflammation is a natural host defensive process that is largely regulated by macrophages during the innate immune response. Mitogen-activated protein kinases (MAPKs) are proline-directed serine and threonine protein kinases that regulate many physiological and pathophysiological cell responses. p38 MAPKs are key MAPKs involved in the production of inflammatory mediators, including tumor necrosis factor-? (TNF-?) and cyclooxygenase-2 (COX-2). p38 MAPK signaling plays an essential role in regulating cellular processes, especially inflammation. In this paper, we summarize the characteristics of p38 signaling in macrophage-mediated inflammation. In addition, we discuss the potential of using inhibitors targeting p38 expression in macrophages to treat inflammatory diseases. PMID:24771982

Yang, Yanyan; Yu, Tao; Sung, Gi-Ho; Yoo, Byong Chul

2014-01-01

254

ARE MACROPHAGES ACTIVATED AND INDUCE PULMONARY INJURY BY INTRACELLULARLY BIOAVAILABLE IRON?  

EPA Science Inventory

ARE MACROPHAGES ACTIVATED AND INDUCE PULMONARY INJURY BY INTRACELLULARLY BIOAVAILABLE IRON? UP Kodavanti1, MCJ Schladweiler1, S Becker2, DL Costa1, P Mayer3, A Ziesenis3, WG Kreyling3, 1ETD, 2HSDivision, NHEERL, USEPA, Research Triangle Park, NC, USA, and 3GSF, Inhalation Biology...

255

In vitro Macrophage Activity: Biphasic Effect of Prolactin and Indirect Evidence of Dopaminergic Modulation  

Microsoft Academic Search

Objective: Prolactin (PRL), a peptide hormone produced by the pituitary gland, is involved in the interaction between the neuroendocrine and immune system. Since dopamine receptor antagonists increase serum levels of PRL, both PRL and dopamine receptors might be involved in the modulation of macrophage activity, providing means of communication between the nervous and immune systems. This study evaluated the effects

Maria I. R. Carvalho-Freitas; Elaine C. Rodrigues-Costa; Antonia G. Nasello; João Palermo-Neto; Luciano F. Felicio

2008-01-01

256

Alternatively Activated Macrophages Elicited by Helminth Infection Can Be Reprogrammed to Enable Microbial Killing1  

E-print Network

a murine model of filarial infection, in which adult nematodes are surgically implanted into the peritoneal at sites of inflammation or infection. Among these signals, cytokines, which can act synergisticallyAlternatively Activated Macrophages Elicited by Helminth Infection Can Be Reprogrammed to Enable

Allen, Judith

257

Effect of antiserotonin antibodies on functional activity of T and B lymphocytes and peritoneal macrophages  

Microsoft Academic Search

Experiments on C57Bl\\/6 mice showed that antiserotonin antibodies injected intraperitoneally in a dose of 25 mg\\/kg or added\\u000a to cell culture in a dose of 10?7 mol\\/ml suppress lymphocyte proliferative response to pokeweed mitogen and stimulate functional activity of macrophages.

T. B. Davydova; V. A. Evseev; V. G. Fomina; L. A. Basharova; O. I. Mikovskaya

1998-01-01

258

A patatin-like protein protects Toxoplasma gondii from degradation in activated macrophages  

E-print Network

A patatin-like protein protects Toxoplasma gondii from degradation in activated macrophages Dana G vacuoles over time, the loss of GRA4 and SAG1 protein staining by immunofluorescence assay plasmid in the 89B7 clone disrupts the promoter of a 3.4 kb mRNA that encodes a predicted 68 kDa protein

Sheridan, Jennifer

259

Signaling role of iron in NF-kappa B activation in hepatic macrophages  

Microsoft Academic Search

Iron is both essential and toxic for cells and impaired iron homeostasis has been shown to cause or potentiate various forms of liver injury. Research in our laboratory suggests that iron also plays a pivotal role in intracellular signaling for NF-kappa B activation in hepatic macrophages (HM). Our results showed: 1) HM from alcohol-fed rats had a increase in the

Shigang Xiong; Hongyun She; Hidekazu Tsukamoto

2004-01-01

260

Model-driven multi-omic data analysis elucidates metabolic immunomodulators of macrophage activation  

SciTech Connect

Macrophages are central players in the immune response, manifesting divergent phenotypes to control inflammation and innate immunity through the release of cytokines and other regulatory factor-dependent signaling pathways. In recent years, the focus on metabolism has been reemphasized as critical signaling and regulatory pathways of human pathophysiology, ranging from cancer to aging, often converge on metabolic responses. Here, we used genome-scale modeling and multi-omics (transcriptomics, proteomics, and metabolomics) analysis to assess metabolic features critical for macrophage functions. We constructed a genome-scale metabolic network for the RAW 264.7 cell line to determine metabolic modulators of macrophage activation. Metabolites well-known to be associated with immunoactivation (e.g., glucose and arginine) and immunosuppression (e.g., tryptophan and vitamin D3) were amongst the most critical effectors. Intracellular metabolic mechanisms linked to critical suppressive effectors were then assessed, identifying a suppressive role for de novo nucleotide synthesis. Finally, the underlying metabolic mechanisms of macrophage activation are identified by analyzing multi-omic data obtained from LPS-stimulated RAW cells in the context of our flux-based predictions. Our study demonstrates metabolism's role in regulating activation may be greater than previously anticipated and elucidates underlying metabolic connections between activation and metabolic effectors.

Bordbar, Aarash; Mo, Monica L.; Nakayasu, Ernesto S.; Rutledge, Alexandra C.; Kim, Young-Mo; Metz, Thomas O.; Jones, Marcus B.; Frank, Bryan C.; Smith, Richard D.; Peterson, Scott N.; Hyduke, Daniel R.; Adkins, Joshua N.; Palsson, Bernhard O.

2012-06-26

261

Propofol Specifically Inhibits Mitochondrial Membrane Potential but Not Complex I NADH Dehydrogenase Activity, Thus Reducing Cellular ATP Biosynthesis and Migration of Macrophages  

Microsoft Academic Search

Propofol is a widely used intravenous anesthetic agent. Our previous study showed that a therapeutic concentration of propofol can modulate macrophage functions. Mitochondria play critical roles in the maintenance of macrophage activities. This study attempted to evaluate further the effects of mitochondria on the propofol-induced suppression of macrophage functions using mouse macrophage-like Raw 264.7 cells as the experimental model. Macrophages

Gong-Jhe Wu; Yu-Ting Tai; Ta-Liang Chen; Li-Ling Lin; Yune-Fang Ueng; Ruei-Ming Chen

2005-01-01

262

[Phagocytosis of Mycobacterium leprae down-regulates anti-microbial activity of murine macrophages against Mycobacterium intracellulare].  

PubMed

Patients with highly bacillated lepromatous leprosy (LL) essentially lack T cell-mediated immune responses specific to Mycobacterium leprae (ML) antigens, resulting in severely impaired host resistance to leprosy bacilli. Such type of immune unresponsiveness characteristic of LL patients is mainly attributable to markedly depressed T cell ability to activate/expand in response to ML antigens. In this study, we examined profiles of antimycobacterial activity of macrophages, which phagocytized leprosy bacilli, because there is another possibility that, in LL patients, host macrophages in the leprosy lesions are impaired in their antimicrobial activity due to their interaction with infected leprosy bacilli, particularly cellular events through binding with and/or internalization of the pathogens, thereby causing the reduction in host resistance to ML pathogens. The present study indicated the following. First, the anti-M. avium complex activity of murine peritoneal macrophages was significantly reduced when they had phagocytosed heat-killed leprosy bacilli. Second, infection of macrophages with leprosy bacilli did not affect macrophage-mediated suppressor activity against T cell proliferative response to Concanavalin A. These findings indicate that macrophage's intracellular signaling pathways that are up-regulated in response to phagocytosis of leprosy bacilli are linked to the signaling cascades participating in macrophage antimicrobial functions, but not cross-talk with those allowing the expression of macrophage's suppressor activity against T cell functions. PMID:23012845

Tatano, Yutaka; Sano, Chiaki; Emori, Masako; Saito, Hajime; Sato, Katsumasa; Shimizu, Toshiaki; Tomioka, Haruaki

2012-09-01

263

Modulation of macrophage function by gamma-irradiation. Acquisition of the primed cell intermediate stage of the macrophage tumoricidal activation pathway  

SciTech Connect

Macrophage activation for tumor cell killing is a multistep pathway in which responsive macrophages interact sequentially with priming and triggering stimuli in the acquisition of full tumoricidal activity. Although this synergistic response of normal macrophages to sequential incubation with activation signals has been well established, characterization of the intermediate stages in this pathway has been difficult, due in large measure to the instability of the intermediate cell phenotypes. We have developed a model system for examination of macrophage-mediated tumor cell lysis, with the use of the murine macrophage tumor cell line RAW 264.7. These cells, like normal macrophages, exhibit a strict requirement for interaction with both interferon-gamma (IFN-gamma, the priming signal) and bacterial lipopolysaccharide (LPS, the triggering signal) in the development of tumor cytolytic activity. In this system, the priming effects of IFN-gamma decay rapidly after withdrawal of this mediator and the cells become unresponsive to LPS triggering. We have recently observed that gamma-irradiation of the RAW 264.7 cells also results in development of a primed activation state for tumor cell killing. The effects of gamma-radiation on the RAW 264.7 cell line are strikingly similar to those resulting from incubation with IFN-gamma, with the exception that the irradiation-induced primed cell intermediate is stable and responsive to LPS triggering for at least 24 hr. Treatment with gamma-radiation also results in increased cell surface expression of major histocompatibility complex-encoded class I antigens; however, class II antigen expression is not induced.

Lambert, L.E.; Paulnock, D.M.

1987-10-15

264

Eosinophils and monocytes produce pulmonary and activation-regulated chemokine, which activates cultured monocytes/macrophages.  

PubMed

Pulmonary and activation-regulated chemokine (PARC/CCL18) belongs to the family of CC chemokines and shares 61% sequence identity with monocyte inflammatory protein (MIP)-1alpha. Produced by dendritic cells and macrophages primarily in the lung, PARC is known to be chemotactic for T cells. Because PARC's biological function is largely unknown, we screened various leukocyte populations for PARC expression and for response to PARC, with the idea that the cellular source may link PARC to disease states in which it may be involved. Here we report that eosinophils obtained from individuals with mild eosinophilia express PARC as assessed by RT-PCR on eosinophil RNA. The eosinophil preparations were free of monocytes, a known source of PARC, and no RT-PCR product was obtained from neutrophils. Furthermore, PARC protein was detected by ELISA in the supernatants of eosinophils from seven of nine donors and in higher concentration in the supernatants of monocytes on day 1 of culture. Purified recombinant PARC activated human monocytes/macrophages kept in culture for 3-4 days but not freshly isolated monocytes. The threshold dose for Ca(2+) mobilization as determined fluorometrically in indo 1-AM-labeled monocytes was 5 nM; maximal response was reached with approximately 50 nM PARC. PARC was chemotactic for these cultured monocytes and caused actin polymerization determined by FITC-phalloidin binding and fluorescence-activated cell sorting analysis. In contrast, PARC activated neither neutrophils nor eosinophils. Eosinophil production of PARC, its chemotactic effect on monocytes and lymphocytes, and PARC's previously described localization to the lung suggest that this chemokine might play a role in pulmonary leukocyte trafficking. PMID:12716654

Schraufstatter, Ingrid; Takamori, Hiroshi; Sikora, Lyudmila; Sriramarao, P; DiScipio, Richard G

2004-03-01

265

In vitro stimulation of alveolar macrophage metabolic activity by polystyrene in the absence of phagocytosis.  

PubMed Central

The technique of lucigenin-dependent phagocytic chemiluminescence was used to investigate the stimulation of metabolic activity in human alveolar macrophages on contact with polystyrene. The results were similar to those obtained using a spectrophotometric assay of superoxide release based on ferricytochrome C reduction. There was a marked stimulation of metabolic activity in the alveolar macrophages on incubation at 37 degrees in polystyrene vials which was shown to be due to contact with and adherence to the polystyrene. This could be reduced by the addition of gelatin or foetal calf serum without preventing the ability of the cells to respond to opsonized particles. By using several metabolic inhibitors it was shown that lucigenin-dependent chemiluminescence was associated with the release of superoxide at the time of adherence. The implications of these findings are discussed and it is suggested that the stimulation of alveolar macrophage metabolic activity by contact with polystyrene can contribute to the observed difference between alveolar macrophage and polymorphonuclear leucocyte oxygen consumption in the absence of phagocytosis. PMID:6261780

Williams, A. J.; Cole, P. J.

1981-01-01

266

Resistance of LPS-activated bone marrow derived macrophages to apoptosis mediated by dexamethasone.  

PubMed

Glucocorticoids (GC) display pleiotropic effects on the immune system. Macrophages are a major target for GC action. Here we show that dexamethasone (DEX), a synthetic GC, decreased viability of naïve bone marrow-derived macrophages (BMDM), involving an apoptotic mechanism. Administration of DEX together with lipopolysaccharide (LPS) protected BMDM against DEX-mediated cell death, suggesting that activated BMDM respond to DEX differently than naïve BMDM. An insight to the molecular basis of LPS actions was provided by a 7 fold increase in mRNA levels of glucocorticoid receptor beta (GR?), a GR dominant-negative splice variant which inhibits GR?'s transcriptional activity. LPS did not inhibit all DEX-mediated effects on BMDM; DEX significantly reduced the percentage of BMDM expressing high levels of the cell surface markers F4/80 and CD11b and led to a decrease in macrophage inflammatory protein 1 alpha (MIP1-?) mRNA and protein levels. These two DEX-mediated effects were not prevented by LPS. Our finding that LPS did not reduce the DEX-induced elevation of glucocorticoid-induced leucine zipper (GILZ), a mediator of GCs anti-inflammatory actions, may provide an underlying mechanism. These findings enable a better understanding of clinical states, such as sepsis, in which macrophages are activated by endotoxins and treatment by GCs is considered. PMID:24608810

Haim, Yasmin Ohana; Unger, Naamit Deshet; Souroujon, Miriam C; Mittelman, Moshe; Neumann, Drorit

2014-01-01

267

Utility and safety of LPS-based fermented flour extract as a macrophage activator.  

PubMed

The immune system is part of the homeostasis system. Our research is focused on ways to maintain health, with an emphasis on the role of macrophages. We have hypothesized that tissue macrophages form a systemic network which we believe contributes to the homeostasis system, and have named it the 'macrophage network.' This network creates a dynamic equilibrium situation where macrophages control homeostasis. Our research is based on this macrophage network theory as we believe that the innate immune system provides the foundation for the homeostasis system. As part of our research, we have demonstrated that macrophage activation can provide protection and therapeutic effects for various diseases. Therefore, we have also focused on lipopolysaccharide (LPS). We proved that the LPS of Pantoea agglomerans (which we have named IP-PA1) was useful in preventing various health disorders and in restoring health when administered via the oral or transdermal route. We also developed a 'fermented flour extract', which consists largely of IP-PA1. For LPS to become a valuable commodity, it is very important to provide assurance about safety (when administered orally or transdermally) to build confidence. For this reason, we tested fermented flour extract (in which the major component was IP-PA1) to confirm that it was safe. The results of these safety trials confirmed that oral and transdermal administration of fermented flour extract was very safe. Thus, we believe that fermented flour extract is a new substance that will have applications in health food, cosmetics, animal feeds, fisheries feeds and drugs industries. PMID:19414320

Taniguchi, Yoshie; Yoshioka, Noriko; Nishizawa, Takashi; Inagawa, Hiroyuki; Kohchi, Chie; Soma, Gen-Ichiro

2009-03-01

268

Regulation of Activation-associated MicroRNA Accumulation Rates during Monocyte-to-macrophage Differentiation.  

PubMed

Circulating monocytes recruited to tissues can differentiate into macrophages and adopt unique gene expression programs in response to environmental cues. We recently described the regulated expression of several microRNAs (miRNAs) in polarized human monocyte-derived macrophages (MDMs). Basal expression of these activation-associated miRNAs was low in monocytes relative to MDMs. As development occurs in the context of specific cellular environments, we hypothesized that the rate of miRNA accumulation would be modified in the presence of microbial or cellular products during monocyte-to-macrophage differentiation. Indeed, LPS treatment augmented the accumulation of miR-146a and miR-155, whereas IL-4 treatment augmented the accumulation of miR-193b and miR-222 during development. In contrast, some stimuli repressed accumulation of specific miRNAs including interferons (IFNs) (miR-27a, miR-125a-5p, and miR-222), IL-4 (miR-125a-5p), and LPS (miR-27a). RT-PCR-based expression profiling of monocytes differentiated with distinct methods showed that activation-associated miRNAs and markers of macrophage polarization were substantially altered in MDMs differentiated in the presence of non-monocytic peripheral blood mononuclear cells due in part to NF-?B and STAT1 pathway activation. Expression of several of these miRNAs was regulated at a preprocessing step because the expression of the primary miRNAs, but not Dicer, correlated with mature miRNA expression. We conclude that a set of miRNAs is regulated during MDM differentiation, and the rate is uniquely modified for each miRNA by environmental factors. The low basal expression of activation-associated miRNAs in monocytes and their dynamic rates of accumulation during MDM differentiation permit monocytes to tailor miRNA profiles in peripheral tissues during differentiation to macrophages. PMID:25148686

Eigsti, Renee L; Sudan, Bayan; Wilson, Mary E; Graff, Joel W

2014-10-10

269

In Vivo and In Vitro Immunomodulatory Potential of Swertiamarin Isolated from Enicostema axillare (Lam.) A. Raynal That Acts as an Anti-inflammatory Agent.  

PubMed

Swertiamarin is a secoiridoid glycoside found in Enicostema axillare (Lam) A. Raynal, a medicinal plant used as a depurative in the Indian system of traditional medicine. The present study evaluated the immunomodulatory activity of isolated swertiamarin. In vivo immunomodulatory activity of swertiamarin (2, 5, and 10 mg/kg b.w.) was evaluated in a model of sheep red blood cells (SRBC) by assessing its effect on organ weight, hemagglutinating antibody titer (HA), plaque-forming cells (PFC), quantitative hemolysis of SRBC, and delayed type hypersensitivity (DTH). In vitro immunomodulatory potential was studied on isolated splenocytes, neutrophils, and peritoneal macrophages. In silico immunomodulatory effects were evaluated by docking of swertiamarin on proinflammatory cytokines to confirm its potential. In in vivo studies, the animals treated with swertiamarin showed a significant (P???0.05) increase in antibody titer, plaque-forming cells, and also in weight of the thymus and spleen. A decreased response to DTH reaction was recorded with the treatment of swertiamarin. In in vitro studies, treatment with swertiamarin modulated the messenger RNA (mRNA) and protein expression of IFN-?, IL-10, and IL-4 significantly (P???0.05) and also favored Th2-mediated response on concanavalin A (Con A)-induced splenocytes. The compound inhibited the release of free radicals significantly (P???0.05) in phytohemagglutinin (PHA)-induced neutrophils and also ameliorated the mRNA and protein expression of proinflammatory cytokines (TNF-?, IL-1?, and IL-6) in lipopolysaccharide (LPS)-induced macrophages. In in silico, the best docked pose of swertiamarin with the target proteins (TNF-?, IL-1?, and IL-6) was confirmed that swertiamarin acted as an anti-inflammatory mediator. PMID:24736879

Saravanan, S; Pandikumar, P; Babu, N Prakash; Islam, V I Hairul; Thirugnanasambantham, K; Paulraj, M Gabriel; Balakrishna, K; Ignacimuthu, S

2014-10-01

270

Stressor-Induced Increase in Microbicidal Activity of Splenic Macrophages Is Dependent upon Peroxynitrite Production  

PubMed Central

Exposing mice to a social stressor called social disruption (SDR) that involves repeated social defeat during intermale aggression results in increased circulating cytokines, such as interleukin-1? (IL-1?) and IL-1?, and increased reactivity of splenic CD11b+ macrophages to inflammatory stimuli. For example, upon lipopolysaccharide stimulation, macrophages from stressor-exposed mice produce higher levels of cytokines than do cells from nonstressed controls. Moreover, the SDR stressor enhances the ability of these macrophages to kill Escherichia coli both in vitro and in vivo, through a Toll-like receptor 4-dependent mechanism. The present study tested the hypothesis that stressor-enhanced bacterial killing is due to increases in the production of peroxynitrite. Male mice were exposed to the SDR stressor or were left undisturbed. Upon stimulation with E. coli, splenic macrophages from SDR-exposed mice expressed significantly increased levels of inducible nitric oxide synthase mRNA and produced higher levels of peroxynitrite. Blocking the production of peroxynitrite abrogated the SDR-induced increase in microbicidal activity. Studies in IL-1 receptor type 1 knockout mice indicated that the increased microbicidal activity and peroxynitrite production was dependent upon IL-1 signaling. These data confirm and extend the importance of IL-1 signaling for stressor-induced immunopotentiation; the finding that inhibiting superoxide or nitric oxide production inhibits both peroxynitrite production and killing of E. coli demonstrates that peroxynitrite mediates the stressor-induced increase in bacterial killing. PMID:22825446

Allen, Rebecca G.; Lafuse, William P.; Powell, Nicole D.; Webster Marketon, Jeanette I.; Stiner-Jones, La'Tonia M.; Sheridan, John F.

2012-01-01

271

Identification of a thrombin sequence with growth factor activity on macrophages  

SciTech Connect

In contrast to fibroblasts, the exposure of G0/G1-arrested J774 cells, a murine macrophage-like tumor cell line, with either active or esterolytically inactive diisopropyl phosphorofluoridate-conjugated -thrombin results in a mitogenic response as measured by increased (TH)thymidine incorporation. This response to thrombin is optimal at 10 nM and is specifically blocked by hirudin, a high-affinity thrombin inhibitor. When prethrombin 1 is cleaved with cyanogen bromide, a fragment (peptide CB67-129) is produced that, like the parent thrombin molecule, is mitogenic for J774 cells but not for fibroblasts. Limited tryptic digests of this fragment retain the ability to stimulate macrophages - a function that can be mimicked by a synthetic tetradecapeptide homologue of CB67-129 but not by any of a series of well-known growth promoters. The mitogenic effects of this peptide are not limited to J774 cells but can be expressed in other macrophage-like tumor cells lines. In addition to increased (TH)thymidine incorporation, the synthetic B chain peptide stimulates cell proliferation as evidenced by a dose-dependent increase in total protein per culture well and cell number. The authors conclude that the thrombin molecule contains a macrophage growth factor domain that is separate and distinct from its active center. Thus, thrombin, in addition to its major role in hemostasis and thrombosis, may also have important functions in such basic processes as the inflammatory response and monocytopoiesis.

Bar-Shavit, R.; Kahn, A.J.; Mann, K.G.; Wilner, G.D.

1986-02-01

272

Quercetin-3-O-glucuronide induces ABCA1 expression by LXR? activation in murine macrophages  

SciTech Connect

Highlights: •The major circulating quercetin metabolite (Q3GA) activated LXR?. •Q3GA induced ABCA1 via LXR? activation in macrophages. •Nelumbo nucifera leaf extracts contained quercetin glycosides. •N. nucifera leaf extract feeding elevated HDLC in mice. -- Abstract: Reverse cholesterol transport (RCT) removes excess cholesterol from macrophages to prevent atherosclerosis. ATP-binding cassette, subfamily A, member 1 (ABCA1) is a crucial cholesterol transporter involved in RCT to produce high density lipoprotein-cholesterol (HDLC), and is transcriptionally regulated by liver X receptor alpha (LXR?), a nuclear receptor. Quercetin is a widely distributed flavonoid in edible plants which prevented atherosclerosis in an animal model. We found that quercetin-3-O-glucuronide (Q3GA), a major quercetin metabolite after absorption from the digestive tract, enhanced ABCA1 expression, in vitro, via LXR? in macrophages. In addition, leaf extracts of a traditional Asian edible plant, Nelumbo nucifera (NNE), which contained abundant amounts of quercetin glycosides, significantly elevated plasma HDLC in mice. We are the first to present experimental evidence that Q3GA induced ABCA1 in macrophages, and to provide an alternative explanation to previous studies on arteriosclerosis prevention by quercetin.

Ohara, Kazuaki, E-mail: Kazuaki_Ohara@kirin.co.jp [Research Laboratories for Health Science and Food Technologies, Kirin Company Limited, 1-13-5 Fukuura, Kanazawa-ku, Yokohama 236-0004 (Japan)] [Research Laboratories for Health Science and Food Technologies, Kirin Company Limited, 1-13-5 Fukuura, Kanazawa-ku, Yokohama 236-0004 (Japan); Wakabayashi, Hideyuki [Laboratory for New Product Development, Kirin Beverage Company Limited, 1-17-1 Namamugi, Tsurumi-ku, Yokohama 230-8628 (Japan)] [Laboratory for New Product Development, Kirin Beverage Company Limited, 1-17-1 Namamugi, Tsurumi-ku, Yokohama 230-8628 (Japan); Taniguchi, Yoshimasa [Research Laboratories for Health Science and Food Technologies, Kirin Company Limited, 1-13-5 Fukuura, Kanazawa-ku, Yokohama 236-0004 (Japan)] [Research Laboratories for Health Science and Food Technologies, Kirin Company Limited, 1-13-5 Fukuura, Kanazawa-ku, Yokohama 236-0004 (Japan); Shindo, Kazutoshi [Department of Food and Nutrition, Japan Women’s University, 2-8-1 Mejirodai, Bunkyo-ku, Tokyo 112-8681 (Japan)] [Department of Food and Nutrition, Japan Women’s University, 2-8-1 Mejirodai, Bunkyo-ku, Tokyo 112-8681 (Japan); Yajima, Hiroaki [Research Laboratories for Health Science and Food Technologies, Kirin Company Limited, 1-13-5 Fukuura, Kanazawa-ku, Yokohama 236-0004 (Japan)] [Research Laboratories for Health Science and Food Technologies, Kirin Company Limited, 1-13-5 Fukuura, Kanazawa-ku, Yokohama 236-0004 (Japan); Yoshida, Aruto [Central Laboratories for Key Technologies, Kirin Company Limited, 1-13-5 Fukuura, Kanazawa-ku, Yokohama 236-0004 (Japan)] [Central Laboratories for Key Technologies, Kirin Company Limited, 1-13-5 Fukuura, Kanazawa-ku, Yokohama 236-0004 (Japan)

2013-11-29

273

Activated macrophages induce structural abnormalities of the T cell receptor-CD3 complex  

PubMed Central

The mechanism of the structural alterations of the T cell receptor (TCR)-CD3 complex, which appear to be greatly responsible for immunosuppression in the tumor-bearing status, was investigated in tumor-bearing mice. Splenic T cells from tumor-bearing hosts lost the expression of the CD3 zeta chain without being replaced by FcR gamma, despite the normal expression of other components of the TCR complex. Tumor growth induced the accumulation of non-T, non-B cells in the spleen in correlation with the loss of zeta. Those cells were found to be macrophages that were able to induce the loss of zeta, as well as structural changes of CD3 gamma delta epsilon, even in freshly isolated normal T cells by cell contact-dependent interaction. More importantly, macrophages activated with zymosan A+LPS but not residential macrophages were able to induce the similar abnormality of the TCR complex. These results indicate that macrophages in certain activation stages play a crucial role in causing an abnormal TCR complex in tumor- bearing conditions, as well as in regulating the structure of the TCR complex in immune responses. PMID:7722462

1995-01-01

274

The ?-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages.  

PubMed

The ketone body ?-hydroxybutyrate (BHB) is an endogenous factor protecting against stroke and neurodegenerative diseases, but its mode of action is unclear. Here we show in a stroke model that the hydroxy-carboxylic acid receptor 2 (HCA2, GPR109A) is required for the neuroprotective effect of BHB and a ketogenic diet, as this effect is lost in Hca2(-/-) mice. We further demonstrate that nicotinic acid, a clinically used HCA2 agonist, reduces infarct size via a HCA2-mediated mechanism, and that noninflammatory Ly-6C(Lo) monocytes and/or macrophages infiltrating the ischemic brain also express HCA2. Using cell ablation and chimeric mice, we demonstrate that HCA2 on monocytes and/or macrophages is required for the protective effect of nicotinic acid. The activation of HCA2 induces a neuroprotective phenotype of monocytes and/or macrophages that depends on PGD2 production by COX1 and the haematopoietic PGD2 synthase. Our data suggest that HCA2 activation by dietary or pharmacological means instructs Ly-6C(Lo) monocytes and/or macrophages to deliver a neuroprotective signal to the brain. PMID:24845831

Rahman, Mahbubur; Muhammad, Sajjad; Khan, Mahtab A; Chen, Hui; Ridder, Dirk A; Müller-Fielitz, Helge; Pokorná, Barbora; Vollbrandt, Tillman; Stölting, Ines; Nadrowitz, Roger; Okun, Jürgen G; Offermanns, Stefan; Schwaninger, Markus

2014-01-01

275

Myeloid-Derived Tissue-Type Plasminogen Activator Promotes Macrophage Motility through FAK, Rac1, and NF-?B Pathways.  

PubMed

Macrophage accumulation is one of the hallmarks of progressive kidney disease. Tissue-type plasminogen activator (tPA) is known to promote macrophage infiltration and renal inflammation during chronic kidney injury. However, the underlying mechanism remains largely unknown. We examined the role of tPA in macrophage motility in vivo by tracking fluorescence-labeled bone marrow-derived macrophages, and found that tPA-deficient mice had markedly fewer infiltrating fluorescence-labeled macrophages than the wild-type (WT) mice. Experiments in bone marrow chimeric mice further demonstrated that myeloid cells are the main source of endogenous tPA that promotes macrophage migration. In vitro studies showed that tPA promoted macrophage motility through its CD11b-mediated protease-independent function; and focal adhesion kinase (FAK), Rac-1, and NF-?B were indispensable to tPA-induced macrophage migration as either infection of FAK dominant-negative adenovirus or treatment with a Rac-1-specific inhibitor or NF-?B inhibitor abolished the effect of tPA. Moreover, ectopic FAK mimicked tPA and induced macrophage motility. tPA also activated migratory signaling in vivo. The accumulation of phospho-FAK-positive CD11b macrophages in the obstructed kidneys from WT mice was clearly attenuated in tPA knockout mice, which also displayed lower Rac-1 activity than their WT counterparts. Therefore, our results indicate that myeloid-derived tPA promotes macrophage migration through a novel signaling cascade involving FAK, Rac-1, and NF-?B. PMID:25131752

Lin, Ling; Jin, Yang; Mars, Wendy M; Reeves, W Brian; Hu, Kebin

2014-10-01

276

Activation of macrophages stimulated by the bengkoang fiber extract through toll-like receptor 4.  

PubMed

Bengkoang (Pachyrhizus erosus (L.) Urban) is an edible root tuber containing fairly large amounts of carbohydrates and crude fibers. Our previous studies showed that the bengkoang fiber extract (BFE) stimulates activation of macrophages, leading to induction of phagocytotic activity and cytokine production. In the present study we investigated the mechanism underlying activation of murine macrophages by BFE. BFE increased production of TNF-?, IL-6, and nitric oxide by J774.1 cells. In addition BFE also facilitated the gene expression levels of inducible nitric oxide synthase. We examined the effect of a TLR4 inhibitor on cytokine production to investigate the membrane receptor of macrophage activation by BFE. Treatment of J774.1 cells with the TLR4 inhibitor significantly inhibited production of IL-6 and TNF-?, suggesting that TLR4 is the target membrane receptor for BFE. The main signal molecules located downstream of TLR4 such as JNK, p38, ERK, and NF-?B were activated by BFE treatment. The immunostimulatory effect of BFE was cancelled by the pectinase treatment, suggesting that the active ingredient in BFE is pectin-like molecules. Overall results suggested that BFE activates J774.1 cells via the MAPK and NF-?B signaling pathways. PMID:24770453

Kumalasari, Ika Dyah; Nishi, Kosuke; Putra, Agus Budiawan Naro; Sugahara, Takuya

2014-07-25

277

A Novel in vitro Human Macrophage Model to Study the Persistence of Mycobacterium tuberculosis Using Vitamin D3 and Retinoic Acid Activated THP-1 Macrophages  

PubMed Central

Mycobacterium tuberculosis (Mtb) replicates within the human macrophages and we investigated the activating effects of retinoic acid (RA) and vitamin D3 (VD) on macrophages in relation to the viability of intracellular Mtb. A combination of these vitamins (RAVD) enhanced the levels of DC-SIGN and mannose receptors on THP-1 macrophages that increased mycobacterial uptake but inhibited the subsequent intracellular growth of Mtb by inducing reactive oxygen species and autophagy. RAVD also enhanced antigen presenting and chemotactic receptors on THPs suggesting an activated phenotype for RAVD activated THPs. RAVD mediated activation was also associated with a marked phenotypic change in Mtb infected THPs that fused with adjacent THPs to form multinucleated giant cells (MNGCs). Typically, MNGCs occurred over 30?days of in vitro culture and contained non-replicating persisting Mtb for more than 60?days in culture. Latent tuberculosis occurs in over a third of mankind and we propose that RAVD mediated induction of persistent Mtb within human macrophages provides a novel model to develop therapeutic approaches and investigate pathogenesis of latency. PMID:21747789

Estrella, Jaymie L.; Kan-Sutton, Celestine; Gong, Xing; Rajagopalan, Malini; Lewis, Dorothy E.; Hunter, Robert L.; Eissa, N. Tony; Jagannath, Chinnaswamy

2010-01-01

278

Oxidized LDL Regulates Macrophage Gene Expression through Ligand Activation of PPAR?  

Microsoft Academic Search

Macrophage uptake of oxidized low-density lipoprotein (oxLDL) is thought to play a central role in foam cell formation and the pathogenesis of atherosclerosis. We demonstrate here that oxLDL activates PPAR?-dependent transcription through a novel signaling pathway involving scavenger receptor-mediated particle uptake. Moreover, we identify two of the major oxidized lipid components of oxLDL, 9-HODE and 13-HODE, as endogenous activators and

Laszlo Nagy; Peter Tontonoz; Jacqueline G. A Alvarez; Hongwu Chen; Ronald M Evans

1998-01-01

279

Helminth 2Cys peroxiredoxin drives Th2 responses through a mechanism involving alternatively activated macrophages  

Microsoft Academic Search

During helminth infections, alternatively activated macrophages (AAMacs) are key to promoting Th2 responses and suppressing Th1-driven inflamma- tory pathology. Th2 cytokines IL-4 and\\/or IL-13 are believed to be important in the induction and activation of AAMacs. Using murine models for the helminth infections caused by Fasciola hepatica (Fh) and Schisto- soma mansoni (Sm), we show that a secreted antioxidant, peroxiredoxin

Sheila Donnelly; Colin M. Stack; Sandra M. O'Neill; Ahmed A. Sayed; David L. Williams; John P. Dalton

2008-01-01

280

Macrophage-mediated activation of camptothecin analogue T-2513-carboxymethyl dextran conjugate (T-0128): possible cellular mechanism for antitumor activity.  

PubMed

Camptothecin (CPT) analogue T-2513-carboxymethyl (CM) dextran conjugate (T-0128) suppressed human tumor xenografts that were refractory to CPTs. This improvement was explained by its altered pharmacokinetics, but the cellular mechanism of action is still not clear. For this reason, in the present study we examined the determinants of T-0128 action at the cellular level. In vitro tests showed that T-0128 was inactive, indicating that the requirement for its activity lies in the release of linked T-2513, accompanied by the cellular uptake of the conjugate. The accumulation varied between cell lines: tumor cells, including Walker-256 carcinoma and B16 melanoma, showed only a marginal uptake and an undetectable drug release in the medium. In contrast, macrophage-like cells, such as J774.1, internalized T-0128 very efficiently, and liberated T-2513. With regard to the mode of accumulation, fluid-phase pinocytosis seems to be a key factor based on the followings: a similar cell-specificity existed in the uptake of FITC dextran, a marker of fluid-phase pinocytosis. Also, the macrophage uptake of T-0128 increased almost linearly with its medium concentration and was insensitive to dextran sulfate, a ligand for macrophage scavenger receptor. Comparative efficacy studies of T-0128 in the presence and absence of macrophages demonstrated that macrophages increased the efficacy of T-0128. The enhancement could be explained in terms of increases in the amount of released T-2513. Overall, these results lead us to the conclusion that T-0128 acts like a Trojan horse with the help of macrophages: T-0128 is taken up by macrophages in tumor tissues, and the liberated T-2513 kills tumor cells. PMID:11102679

Harada, M; Imai, J; Okuno, S; Suzuki, T

2000-12-01

281

Toxoplasma gondii infection of activated J774-A1 macrophages causes inducible nitric oxide synthase degradation by the proteasome pathway.  

PubMed

Classically activated macrophages produce nitric oxide (NO), which is a potent microbicidal agent. NO production is catalyzed by inducible nitric oxide synthase (iNOS), which uses arginine as substrate producing NO and citruline. However, it has been demonstrated that NO production is inhibited after macrophage infection of Toxoplasma gondii, the agent of toxoplasmosis, due to iNOS degradation. Three possible iNOS degradation pathways have been described in activated macrophages: proteasome, calpain and lysosomal. To identify the iNOS degradation pathway after T. gondii infection, J774-A1 macrophage cell line was activated with lipopolysaccharide and interferon-gamma for 24 h, treated with the following inhibitors, lactacystin (proteasome), calpeptin (calpain), or concanamycin A (lysosomal), and infected with the parasite. NO production and iNOS expression were evaluated after 2 and 6 h of infection. iNOS was degraded in J774-A1 macrophages infected with T. gondii. However, treatment with lactacystin maintained iNOS expression in J774-A1 macrophages infected for 2 h by T. gondii, and after 6 h iNOS was localized in aggresomes. iNOS was degraded after parasite infection of J774-A1 macrophages treated with calpeptin or concanamycin A. NO production confirmed iNOS expression profiles. These results indicate that T. gondii infection of J774-A1 macrophages caused iNOS degradation by the proteasome pathway. PMID:24845536

Padrão, Juliana da Cruz; Cabral, Gabriel Rabello de Abreu; da Silva, Maria de Fátima Sarro; Seabra, Sergio Henrique; DaMatta, Renato Augusto

2014-10-01

282

Antitumor and immunomodulatory effects of a water-soluble polysaccharide from Lilii Bulbus in mice.  

PubMed

Lilii Bulbus is a popular folk medicine in the worldwide and has attracted great attention due to its bioactivity against respiratory system diseases (include lung cancers). This study was the first report providing in vivo evidences of antitumor potential of the bioactive polysaccharide from Lilii Bulbus. One major fraction (LBP-1) was obtained by purifying the crude polysaccharides extracted from Lilii Bulbus. Chemical characterization analysis indicated that LBP-1 was only a glucan, whose average molecular weight was 30.5 kDa. Intraperitoneal administration of LBP-1 at the doses of 50-200mg/kg significantly inhibited the growth of Lewis lung carcinoma. Moreover, it could also obviously increase macrophage phagocytosis, splenocytes proliferation and cytokine (TNF-?, IL-2, IL-6 and IL-12) production to participate in the antitumor effects. LBP-1 could act as antitumor agent with immunomodulatory activity. PMID:24507317

Sun, Xin; Gao, Rui-Lan; Xiong, Yao-Kang; Huang, Qing-Cheng; Xu, Min

2014-02-15

283

Immunomodulatory effect of Moringa oleifera Lam. extract on cyclophosphamide induced toxicity in mice.  

PubMed

Immunomodulatory effect of ethanolic extract (50%) of M. oleifera leaves (MOE) has been studied in normal and immunosuppressed mice models. Different doses of MOE i.e. 125, 250 and 500 mg/kg body weight of mice were administered orally for 15 days. Cyclophosphamide at a dose of 30 mg/kg body weight was administered orally for the next 3 days. On day 16 and 19, hematological parameters like white blood cell (WBC) count, red blood cell (RBC) count, haemoglobin level (Hb), percent neutrophils and organ weight were recorded. Effect of MOE on phagocytic activity of mice macrophages was determined by carbon clearance test. MOE showed significant dose dependent increase in WBC, percent neutrophils, weight of thymus and spleen along with phagocytic index in normal and immunosuppressed mice. The results indicate that MOE significantly reduced cyclophosphamide induced immunosuppression by stimulating both cellular and humoral immunity. PMID:21117458

Gupta, Anamika; Gautam, Manish K; Singh, Rahul K; Kumar, M Vijay; Rao, Ch V; Goel, R K; Anupurba, Shampa

2010-11-01

284

Dectin-1-Dependent LC3 Recruitment to Phagosomes Enhances Fungicidal Activity in Macrophages.  

PubMed

Autophagy has been postulated to play role in mammalian host defense against fungal pathogens, although the molecular details remain unclear. Here, we show that primary macrophages deficient in the autophagic factor LC3 demonstrate diminished fungicidal activity but increased cytokine production in response to Candida albicans stimulation. LC3 recruitment to fungal phagosomes requires activation of the fungal pattern receptor dectin-1. LC3 recruitment to the phagosome also requires Syk signaling but is independent of all activity by Toll-like receptors and does not require the presence of the adaptor protein Card9. We further demonstrate that reactive oxygen species generation by NADPH oxidase is required for LC3 recruitment to the fungal phagosome. These observations directly link LC3 to the inflammatory pathway against C. albicans in macrophages. PMID:24842831

Tam, Jenny M; Mansour, Michael K; Khan, Nida S; Seward, Michael; Puranam, Sravanthi; Tanne, Antoine; Sokolovska, Anna; Becker, Christine E; Acharya, Mridu; Baird, Michelle A; Choi, Augustine M K; Davidson, Michael W; Segal, Brahm H; Lacy-Hulbert, Adam; Stuart, Lynda M; Xavier, Ramnik J; Vyas, Jatin M

2014-12-01

285

Complement Activation by CpG in a Human Whole Blood Loop System: Mechanisms and Immunomodulatory Effects1  

PubMed Central

Phosphorothioate oligodeoxynucleotides can activate complement, and experimental murine studies have revealed differential effects upon simultaneous TLR stimulation and complement activation compared with either event alone. We set out to investigate the immune stimulatory effects of CpG 2006 in fresh non-anticoagulated human blood with or without presence of active complement. We also sought to elucidate the mechanism behind complement activation upon stimulation with phosphorothioate CpG 2006. In a human blood loop system, both backbone and sequence-specific effects by CpG were counteracted by selective inhibition of C3. Furthermore, DNA backbone-mediated CD40 and CD83 expression on monocytes and sequence-specific IL-6 and TNF production were reduced by complement inhibition. CpG-induced complement activation occurred via either the classical or the alternative pathway and deposits of both IgM and properdin, two activators of complement, were detected on CpG after incubation with EDTA plasma. Quartz crystal microbalance with dissipation monitoring demonstrated alternative pathway convertase build-up onto CpG as a likely pathway to initiate and sustain complement activation. Specific inhibition of C3 suppressed CpG 2006 uptake into monocytes indicating that C3 fragments are involved in CpG internalization. The interplay between complement and TLR9 signaling demonstrated herein warrants further investigation. PMID:19864604

Mangsbo, Sara M.; Sanchez, Javier; Anger, Kerstin; Lambris, John D.; Ekdahl, Kristina Nilsson; Loskog, Angelica S.; Nilsson, Bo; Totterman, Thomas H.

2010-01-01

286

NOX2?: A Novel Splice Variant of NOX2 That Regulates NADPH Oxidase Activity in Macrophages  

PubMed Central

Nox2 oxidase is one isoform in a family of seven NADPH oxidases that generate reactive oxygen species (ROS) and thereby contribute to physiological and pathological processes including host defense, redox signaling and oxidative tissue damage. While alternative mRNA splicing has been shown to influence the activity of several Nox-family proteins, functionally relevant splice variants of Nox2 have not previously been identified. We immunoscreened several mouse tissues and cells for the presence of truncated Nox2 proteins and identified a 30 kDa protein in lung, spleen and macrophages. RT-PCR analysis of mRNA from primary and immortalised (RAW264.7) mouse macrophages, and from human alveolar macrophages, identified a truncated Nox2 transcript which, upon sequence analysis, was found to be a product of the ‘exon skipping’ mode of alternative splicing, lacking exons 4–10 of the Nox2 gene. The predicted protein is comparable in size to that identified by immunoscreening and contains two transmembrane helices and an extended cytosolic C-terminus with binding sites for NADPH and the Nox organiser protein p47phox. Importantly, selective siRNA-mediated knockdown of the transcript reduced expression of the 30 kDa protein in macrophages, and suppressed phorbol ester-stimulated ROS production by 50%. We thus provide the first evidence that Nox2 undergoes alternative mRNA splicing to yield a 30 kDa protein – herein termed Nox2? – that regulates NADPH oxidase activity in macrophages from mice and humans. The discovery of Nox2? paves the way for future examination of its role in physiological and pathological processes. PMID:23118986

Guida, Elizabeth; King, Paul T.; Sobey, Christopher G.; Drummond, Grant R.

2012-01-01

287

Effects of Lycium barbarum extract on production and immunomodulatory activity of the extracellular polysaccharopeptides from submerged fermentation culture of Coriolus versicolor  

Microsoft Academic Search

Polysaccharopeptides (PSPs) from Coriolus versicolor have been used as immunomodulatory and anticancer agents. However, most studies have concentrated on the mycelial PSPs and not those in the fermented broth. On the other hand, Lycium barbarum fruit has been used as a traditional Chinese herbal medicine for two millennia. Its extract contains various nutrients, minerals, and also polysaccharide–protein complexes, which are

Fang-Yi Lin; Yiu-Kay Lai; Hao-Chen Yu; Nan-Yin Chen; Chi-Yue Chang; Hui-Chen Lo; Tai-Hao Hsu

2008-01-01

288

Lysosomes integrate metabolic-inflammatory cross-talk in primary macrophage inflammasome activation.  

PubMed

Macrophage dysfunction and inflammasome activation have been implicated in the pathogenesis of diabetes and its complications. Prolonged inflammation and impaired healing are hallmarks of the diabetic response to tissue injury, and excessive inflammasome activation has been associated in these phenotypes. However, the mechanisms that regulate the inflammasome in response to lipid metabolic and inflammatory stress are incompletely understood. We have shown previously that IL-1? secretion is induced in primary macrophages exposed to the dietary saturated fatty acid palmitate in combination with LPS. In this study, we sought to unravel the mechanisms underlying the activation of this lipotoxic inflammasome. We demonstrate that palmitate-loaded primary macrophages challenged with LPS activate the NLRP3 inflammasome through a mechanism that involves the lysosome. Interestingly, the lysosome was involved in both the regulation of pro-IL-1? levels and its subsequent cleavage/release. The lysosomal protease cathepsin B was required for IL-1? release but not pro-IL-1? production. In contrast, disrupting lysosomal calcium regulation decreased IL-1? release by reducing pro-IL-1? levels. The calcium pathway involved the calcium-activated phosphatase calcineurin, which stabilized IL-1? mRNA. Our findings provide evidence that the lysosome plays a key role in both the priming and assembly phases of the lipostoxic inflammasome. These findings have potential relevance to the hyperinflammatory phenotypes observed in diabetics during tissue damage or infection and identify lysosomes and calcineurin as potential therapeutic targets. PMID:24532802

Weber, Kassandra; Schilling, Joel D

2014-03-28

289

Model-driven multi-omic data analysis elucidates metabolic immunomodulators of macrophage activation  

PubMed Central

Macrophages are central players in immune response, manifesting divergent phenotypes to control inflammation and innate immunity through release of cytokines and other signaling factors. Recently, the focus on metabolism has been reemphasized as critical signaling and regulatory pathways of human pathophysiology, ranging from cancer to aging, often converge on metabolic responses. Here, we used genome-scale modeling and multi-omics (transcriptomics, proteomics, and metabolomics) analysis to assess metabolic features that are critical for macrophage activation. We constructed a genome-scale metabolic network for the RAW 264.7 cell line to determine metabolic modulators of activation. Metabolites well-known to be associated with immunoactivation (glucose and arginine) and immunosuppression (tryptophan and vitamin D3) were among the most critical effectors. Intracellular metabolic mechanisms were assessed, identifying a suppressive role for de-novo nucleotide synthesis. Finally, underlying metabolic mechanisms of macrophage activation are identified by analyzing multi-omic data obtained from LPS-stimulated RAW cells in the context of our flux-based predictions. Our study demonstrates metabolism's role in regulating activation may be greater than previously anticipated and elucidates underlying connections between activation and metabolic effectors. PMID:22735334

Bordbar, Aarash; Mo, Monica L; Nakayasu, Ernesto S; Schrimpe-Rutledge, Alexandra C; Kim, Young-Mo; Metz, Thomas O; Jones, Marcus B; Frank, Bryan C; Smith, Richard D; Peterson, Scott N; Hyduke, Daniel R; Adkins, Joshua N; Palsson, Bernhard O

2012-01-01

290

Molecular Mechanism of Macrophage Activation by Red Ginseng Acidic Polysaccharide from Korean Red Ginseng  

PubMed Central

Red ginseng acidic polysaccharide (RGAP), isolated from Korean red ginseng, displays immunostimulatory and antitumor activities. Even though numerous studies have been reported, the mechanism as to how RGAP is able to stimulate the immune response is not clear. In this study, we aimed to explore the mechanism of molecular activation of RGAP in macrophages. RGAP treatment strongly induced NO production in RAW264.7 cells without altering morphological changes, although the activity was not strong compared to LPS-induced dendritic-like morphology in RAW264.7 cells. RGAP-induced NO production was accompanied with enhanced mRNA levels of iNOS and increases in nuclear transcription factors such as NF-?B, AP-1, STAT-1, ATF-2, and CREB. According to pharmacological evaluation with specific enzyme inhibitors, Western blot analysis of intracellular signaling proteins and inhibitory pattern using blocking antibodies, ERK, and JNK were found to be the most important signaling enzymes compared to LPS signaling cascade. Further, TLR2 seems to be a target surface receptor of RGAP. Lastly, macrophages isolated from RGS2 knockout mice or wortmannin exposure strongly upregulated RGAP-treated NO production. Therefore, our results suggest that RGAP can activate macrophage function through activation of transcription factors such as NF-?B and AP-1 and their upstream signaling enzymes such as ERK and JNK. PMID:22474399

Byeon, Se Eun; Lee, Jaehwi; Kim, Ji Hye; Yang, Woo Seok; Kwak, Yi-Seong; Kim, Sun Young; Choung, Eui Su; Rhee, Man Hee; Cho, Jae Youl

2012-01-01

291

Immunomodulatory effect of prednisolone (PRD) induced soluble suppressor factor(s) (PRD-SSF) on natural killer (NK) cell activity  

SciTech Connect

The authors have previously reported that peripheral blood lymphocytes precultured for 24 hrs with PRD showed significant suppression of their NK activity. Purified HNK-1/sup +/ lymphocytes were treated either directly with PRD or with supernates from allogeneic lymphocytes precultured with 10/sup -6/ to 10/sup -9/M PRD and examined for any inhibition of NK activity. For the NK assay K562 and U937 cell lines were used as targets in a 4 hr /sup 51/Cr release assay. HNK-1/sup +/ lymphocytes precultured with PRD showed significantly lower level of NK activity. In a single cell assay, both HNK-1/sup +/ and HNK-1/sup -/ subpopulations of PBL precultured with PRD also suppressed the target binding and lytic capacity of allogeneic fresh large granular lymphocytes, suggesting that NK cells/T cells or their precursors can be stimulated by PRD to inhibit NK activity. PBL precultured with increasing concentrations of culture supernates containing PRD-SSF showed a dose dependent inhibitory effect of their NK activity. This data suggest that PRD activated suppressor cells function through the release of soluble mediators. These findings may be of clinical significance to patients receiving corticosteroids for a variety of disorders including malignant, autoimmune and atopic diseases.

Nair, M.P.N.; Cilik, J.M.; Schwartz, S.A.

1986-03-01

292

Evaluation of immunomodulatory potential of ethanolic extract of Roscoea procera rhizomes in mice  

PubMed Central

Purpose: The aim of present study was to evaluate immunomodulatory potential of ethanolic extract of Roscoea procera (Zingiberaceae) rhizomes by using delayed-type hypersensitivity (DTH) and carbon clearance method in comparison to standard established immunosuppressant drug, cyclophosphamide (30 mg/kg, i.p.) in mice. Material and Methods: The extract was comprised to acute toxicity (OECD-423 guideline), DTH and carbon clearance method for their immunomodulatory potential. Ethanolic extract of Roscoea procera rhizomes administered orally at doses 300 mg/kg and 600 mg/kg, p.o. to mice. Result and Conclusion: Result of our study revealed that, the foot pat thickness of ethanolic extract group (P<0.05) significantly enhanced the production of circulating antibody titre in response to Sheep red blood cells (SRBC) and phagocytic functions of mononuclear macrophages and non-specific immunity. Result were also supported by serological and haematological tests data. Hence, the present investigation reveals that, ethanolic extract of Roscoea procera rhizomes possesses immunostimulant properties. Further studies to identify the active moieties and elucidation of the mechanism of action are recommended. PMID:21180470

Sahu, Mahesh S.; Mali, Prashant Y.; Waikar, Shekhar B.; Rangari, Vinod D.

2010-01-01

293

Stimulation of lymphocyte anti-melanoma activity by co-cultured macrophages activated by complex homeopathic medication  

PubMed Central

Background Melanoma is the most aggressive form of skin cancer, and the most rapidly expanding cancer in terms of worldwide incidence. Chemotherapeutic approaches to treat melanoma have been uniformly disappointing. A Brazilian complex homeopathic medication (CHM), used as an immune modulator, has been recommended for patients with depressed immune systems. Previous studies in mice have demonstrated that the CHM activates macrophages, induces an increase in the number of leukocytes and improves the murine response against Sarcoma-180. Methods Here we studied the interaction of mouse lymph node lymphocytes, co-cultured in vitro with macrophages in the presence or absence of the CHM, with B16F10 melanoma cells. Results Lymphocytes co-cultured with macrophages in the presence of the CHM had greater anti-melanoma activity, reducing melanoma cell density and increasing the number of lysed tumor cells. There was also a higher proportion of activated (CD25+) lymphocytes with increased viability. Overall, lymphocytes activated by treatment destroyed growing cancer cells more effectively than control lymphocytes. Conclusion Co-culture of macrophages with lymphocytes in the presence of the CHM enhanced the anti-cancer performance of lymphocytes against a very aggressive lineage of melanoma cells. These results suggest that non-toxic therapies using CHMs are a promising alternative approach to the treatment of melanomas. In addition, they are attractive combination-therapy candidates, which may enhance the efficacy of conventional medicines by improving the immune response against tumor cells. PMID:19698142

2009-01-01

294

Anti-inflammatory effects of galangin on lipopolysaccharide-activated macrophages via ERK and NF-?B pathway regulation.  

PubMed

Abstract Inflammation is the major symptom of the innate immune response to microbial infection. Macrophages, immune response-related cells, play a role in the inflammatory response. Galangin is a member of the flavonols and is found in Alpinia officinarum, galangal root and propolis. Previous studies have demonstrated that galangin has antioxidant, anticancer, and antineoplastic activities. However, the anti-inflammatory effects of galangin are still unknown. In this study, we investigated the anti-inflammatory effects of galangin on RAW 264.7 murine macrophages. Galagin was not cytotoxic to RAW 264.7 cells, and nitric oxide (NO) production induced by lipopolysaccharide (LPS)-stimulated macrophages was significantly decreased by the addition of 50??M galangin. Moreover, galangin treatment reduced mRNA levels of cytokines, including IL-1? and IL-6, and proinflammatory genes, such as iNOS in LPS-activated macrophages in a dose-dependent manner. Galangin treatment also decreased the protein expression levels of iNOS in activated macrophages. Galangin was found to elicit anti-inflammatory effects by inhibiting ERK and NF-?B-p65 phosphorylation. In addition, galangin-inhibited IL-1? production in LPS-activated macrophages. These results suggest that galangin elicits anti-inflammatory effects on LPS-activated macrophages via the inhibition of ERK, NF-?B-p65 and proinflammatory gene expression. PMID:25270721

Jung, Yun Chan; Kim, Mi Eun; Yoon, Ju Hwa; Park, Pu Reum; Youn, Hwa-Young; Lee, Hee-Woo; Lee, Jun Sik

2014-12-01

295

Ionizing Radiation Induces Macrophage Foam Cell Formation and Aggregation Through JNK-Dependent Activation of CD36 Scavenger Receptors  

SciTech Connect

Purpose: Irradiated arteries of cancer patients can be associated with atherosclerosis-like lesions containing cholesterol-laden macrophages (foam cells). Endothelial cell damage by irradiation does not completely explain the foam cell formation. We investigated the possible underlying mechanisms for ionizing radiation (IR)-induced foam cell formation. Methods and Materials: Human peripheral blood monocytes were activated by macrophage colony-stimulating factor and then treated with varying doses of IR in vitro in the absence of endothelial cells. Scavenger receptor expression and foam cell formation of IR-treated macrophages were investigated in the presence or absence of oxidized low-density lipoprotein. We also assessed the importance of mitogen-activated protein kinase activity in the macrophage colony-stimulating factor-activated human monocytes (macrophages) for the foam cell formation. Results: We found that IR treatment of macrophage colony-stimulating factor-activated human peripheral blood monocytes resulted in the enhanced expression of CD36 scavenger receptors and that cholesterol accumulated in the irradiated macrophages with resultant foam cell formation in the presence of oxidized low-density lipoprotein. Furthermore, when cultured on collagen gels, human macrophages formed large foam cell aggregates in response to IR. Antibodies against CD36 inhibited the IR-induced foam cell formation and aggregation, indicating that the IR-induced foam cell formation and the subsequent aggregation are dependent on functional CD36. In addition, we found that IR of human macrophages resulted in c-Jun N-terminal kinase activation and that c-Jun N-terminal kinase inhibition suppressed IR-induced CD36 expression and the subsequent foam cell formation and aggregation. Conclusion: Taken together, these results suggest that IR-induced foam cell formation is mediated by c-Jun N-terminal kinase-dependent CD36 activation.

Katayama, Ikuo; Hotokezaka, Yuka [Department of Radiology and Cancer Biology, Nagasaki University School of Dentistry, Nagasaki (Japan); Matsuyama, Toshifumi [Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (Japan); Sumi, Tadateru [Department of Radiology and Cancer Biology, Nagasaki University School of Dentistry, Nagasaki (Japan); Nakamura, Takashi [Department of Radiology and Cancer Biology, Nagasaki University School of Dentistry, Nagasaki (Japan)], E-mail: taku@nagasaki-u.ac.jp

2008-03-01

296

Structure-activity relationship study of taxoids for their ability to activate murine macrophages as well as inhibit the growth of macrophage-like cells.  

PubMed

A series of new taxoids modified at the C-3', C-3'N, C-10, C-2 and C-7 positions has been designed, synthesized and evaluated for their potency to induce NO and TNF production by peritoneal murine macrophages (Mphi) from LPS-responsive C3H/HeN and LPS-hyporesponsive C3H/HeJ strains and human blood cells, and for their ability to inhibit the growth of Mphi-like cell lines J774.1 and J7.DEF3. The SAR-study has shown that the nature of the substituents at these positions have critical effect on the induction of TNF and NO production by Mphi. Positions C-3' and C-10 are the most flexible and an intriguing effect of the length of the substituents at the C-10 position is observed for taxoids bearing a straight chain alkanoyl moiety. An aromatic group at the C-3'N and C-2 positions is required for the activity, while only hydroxyl or acetyl substituents seem to be tolerated at the C-7 position. The natural stereochemistry in the C-13 isoserine side chain of the taxoids is an absolute requirement for macrophage activation. It has also been clearly shown that there is no correlation between the ability of the taxoids to induce TNF/NO production in C3H/HeN Mphi and the cytotoxicity against Mphi-like cells. PMID:12788358

Ojima, Iwao; Fumero-Oderda, Cecilia L; Kuduk, Scott D; Ma, Zhuping; Kirikae, Fumiko; Kirikae, Teruo

2003-07-01

297

Adherent properties and macrophage activation ability of 3 strains of lactic acid bacteria.  

PubMed

Lactic acid bacteria (LAB) must possess probiotic properties in order to be beneficial to humans and animals. The adherent properties, the acid and bile tolerance as well as the macrophage activation ability of isolated LAB strains were investigated in this study. The adhesion was analyzed following heat, acid, trypsin, and sodium periodate treatments. Production of the cytokine tumor necrosis factor-? (TNF-?) by RAW 264.7 macrophages was also measured after stimulation with heat-killed LAB strains. The viable strains of Lactobacillus fermentum AF7, L. acidophilus GG5, and L. plantarum BB9 were able to tightly adhere to the intestinal Caco-2 cells. In addition, the GG5 strain was not affected by heating, acid, trypsin, or sodium periodate treatment. However, the adhesion of strains AF7 and BB9 was reduced significantly by heating and trypsin treatment. This result suggested the GG5 and AF7 or BB9 strains had different cell-surface adherent factors. TNF-? production by the RAW 264.7 macrophages was induced significantly following stimulation with heat-killed LAB at 10(8) CFU/mL in a dose-dependent fashion. In addition, macrophage activity was similar whether the treatment consisted of live probiotics, or probiotics treated with heat, acid, or trypsin. However, the activity was reduced after treating with sonication. These in vitro results showed that the LAB studied possess probiotic characteristics, such as acid or bile tolerance, adherent capability, and immune activation, and may suggest that these LAB strains retain their probiotic activity as they pass through the gastrointestinal tract. PMID:21535686

Lin, Wen-Hsin; Wu, Chi-Rei; Fang, Tony J; Lee, Meng-Shiou; Lin, Kai-Li; Chen, Hsin-Chun; Huang, Shi-Ying; Hseu, You-Cheng

2011-01-01

298

Distinct signal transduction pathways for activation of rabbit alveolar macrophages in vitro by cotton bract tannin.  

PubMed

These experiments were designed to study signal transduction pathways in alveolar macrophages stimulated by condensed tannin or zymosan. Condensed tannins, present in cotton mill dust, alter the host-defense function of alveolar macrophages and may contribute to the pathogenesis of byssinosis. We tried to determine the early steps in signal transduction mechanisms of cell activation by tannin. With the quantification of 51Cr release, we determined that tannin was cytotoxic for the cells after 30 min activation with 130 micrograms for 2 x 10(6) cells. 51Cr release was similar for control cells and zymosan- or 30 micrograms tannin-activated cells. Using the luciferine luciferase reaction, we showed that tannin markedly depleted ATP cell content. In inositol-labeled cells, tannin increased inositolphosphate release in a dose-dependent manner. In lysoPAF-labeled cells, tannin induced synthesis of phosphatidic acid and diglycerides. In the presence of ethanol, the level of tannin-induced phosphatidic acid was slightly reduced, and phosphatidylethanol was synthesized. No phosphatidylethanol was found in alveolar macrophages stimulated by zymosan in the presence of ethanol. GF 109203X, a specific inhibitor of protein kinase C decreased only tannin-induced phosphatidylethanol synthesis. In conclusion, tannin (at 30 or 130 micrograms/ml) activated an inositol phospholipase C in alveolar membranes. Phosphatidylcholine phospholipases C and D were found only at the higher concentration of tannin. PMID:8658514

Prévost, M C; Soulat, J M; Comminges, C; Maury, E; Aslane, R; Cohen-Jonathan, E; Cariven, C; Lauque, D; Chap, H

1996-05-01

299

Nitric oxide increases susceptibility of toll-like receptor-activated macrophages to spreading Listeria monocytogenes  

PubMed Central

SUMMARY Toll-like receptor (TLR) stimulation activates macrophages to resist intracellular pathogens. Yet, the intracellular bacterium Listeria monocytogenes (Lm) causes lethal infections in spite of innate immune cell activation. Lm uses direct cell-cell spread to disseminate within its host. Here, we have shown that TLR-activated macrophages killed cell-free Lm but failed to prevent infection by spreading Lm. Instead, TLR signals increased the efficiency of Lm spread from “donor” to “recipient” macrophages. This enhancement required nitric oxide (NO) production by nitric oxide synthase-2 (NOS2). NO increased Lm escape from secondary vacuoles in recipient cells and delayed maturation of phagosomes containing membrane-like particles that mimic Lm-containing pseudopods. NO also promoted Lm spread during systemic in vivo infection, as inhibition of NOS2 with 1400W reduced spread-dependent Lm burdens in mouse livers. These findings reveal a mechanism by which pathogens capable of cell-cell spread can avoid the consequences of innate immune cell activation by TLR stimuli. PMID:22542147

Cole, Caroline; Thomas, Stacey; Filak, Holly; Henson, Peter M.; Lenz, Laurel L.

2012-01-01

300

Human lung macrophage-derived histamine-releasing activity is due to IgE-dependent factors.  

PubMed

Human lung macrophages obtained from surgical specimens spontaneously secreted a factor(s) (which we term macrophage factor) during 24-hr culture that induced calcium-dependent histamine release from human basophils and lung mast cells. Macrophage factor induced noncytotoxic histamine release from purified (85%) basophils. The kinetics of release were relatively slow and similar to that of anti-IgE. We performed a series of experiments to test the IgE dependence of macrophage factor-induced release. Preincubation of basophils with anti-IgE in calcium-free medium resulted in complete desensitization to macrophage factor-induced histamine release (i.e., when calcium and macrophage factor were added to the basophils, no histamine release occurred), and preincubation with macrophage factor in calcium-free medium resulted in partial desensitization to anti-IgE-induced histamine release. Pretreatment of basophils with pH 3.9 lactic acid buffer, which dissociates basophil IgE from its receptors, markedly reduced the capacity of basophils to release histamine in response to macrophage factor. Basophils that were incubated with IgE myeloma (but not with IgG) after lactic acid treatment partially or completely regained their capacity to release histamine in response to macrophage factor. Fluid-phase IgE myeloma (15 micrograms/ml) (but not IgG) inhibited basophil histamine release induced by two macrophage-derived supernatants, whereas IgE myeloma (200 micrograms/ml) did not inhibit release due to other supernatants. IgE-affinity columns removed the histamine-releasing activity of five macrophage-derived supernatants, and IgG-affinity columns had similar effects. However, neither affinity column removed the histamine-releasing activity of three other macrophage-derived supernatants. On Sephadex G-75 chromatography, nearly all of the histamine-releasing activity migrated as single peak with an apparent m.w. of 18,000. These results suggest that, although macrophage factor are heterogeneous, they are related, as they are a IgE-dependent factors that induce histamine release by interacting with cell surface IgE. These macrophage factors may be responsible for stimulation of basophil/mast cell mediator release in chronic allergic reactions. PMID:2419444

Liu, M C; Proud, D; Lichtenstein, L M; MacGlashan, D W; Schleimer, R P; Adkinson, N F; Kagey-Sobotka, A; Schulman, E S; Plaut, M

1986-04-01

301

Development and characterization of amphotericin B bearing emulsomes for passive and active macrophage targeting.  

PubMed

The antifungal and antileishmanial agent amphotericin B (AmB) has been complexed with lipids to develop a less toxic formulation of AmB. Because lipid particles are phagocytized by the reticuloendothelial system, lipid associated AmB should be concentrated in infected macrophages of liver and spleen and be very effective against visceral leishmaniasis (VL) and systemic fungal infections. Therefore, AmB was formulated in trilaurin based nanosize lipid particles (emulsomes) stabilized by soya phosphatidylcholine (PC) as a new intravenous drug delivery system for macrophage targeting. Emulsomes were prepared by cast film technique followed by sonication to obtain particles of nanometric size range. Formulations were optimized for AmB to lipid ratio, sonication time and PC to trilaurin ratio. Emulsomes were modified by coating them with macrophage-specific ligand (O-palmitoyl mannan, OPM). The surface modified emulsomes and their plain counterparts were characterised for size, shape, lamellarity and entrapment efficiency. Fluorescence microscopy study showed significant localization of plain and coated emulsomes inside the liver and spleen cells of golden hamsters. In vivo organ distribution studies in albino rats demonstrated that extent of accumulation of emulsome entrapped AmB in macrophage rich organs, particularly liver, spleen and lungs was significantly high when compared against the free drug (AmB-deoxycholate or AmB-Doc). The rate and extent of accumulation were found to increase further on ligand anchoring. Further, a significantly higher (P < 0.05) drug concentration in the liver was estimated over a period of 24 h for OPM coated emulsomes than for plain emulsomes. We concluded that OPM coated emulsomes could fuse with the macrophages of liver and spleen due to ligand-receptor interaction and could target the bioactives inside them. The proposed plain and OPM coated emulsome based systems showed excellent potential for passive and active intramacrophage targeting, respectively and the approach could be a successful alternative to the currently available drug regimens of VL and systemic fungal infections. PMID:17454358

Gupta, Swati; Vyas, Suresh P

2007-04-01

302

Increase in Hypotonic Stress-Induced Endocytic Activity in Macrophages via ClC-3  

PubMed Central

Extracellular hypotonic stress can affect cellular function. Whether and how hypotonicity affects immune cell function remains to be elucidated. Macrophages are immune cells that play key roles in adaptive and innate in immune reactions. The purpose of this study was to investigate the role and underlying mechanism of hypotonic stress in the function of bone marrow-derived macrophages (BMDMs). Hypotonic stress increased endocytic activity in BMDMs, but there was no significant change in the expression of CD80, CD86, and MHC class II molecules, nor in the secretion of TNF-? or IL-10 by BMDMs. Furthermore, the enhanced endocytic activity of BMDMs triggered by hypotonic stress was significantly inhibited by chloride channel-3 (ClC-3) siRNA. Our findings suggest that hypotonic stress can induce endocytosis in BMDMs and that ClC-3 plays a central role in the endocytic process. PMID:24850147

Yan, Yutao; Ding, Yu; Ming, Bingxia; Du, Wenjiao; Kong, Xiaoling; Tian, Li; Zheng, Fang; Fang, Min; Tan, Zheng; Gong, Feili

2014-01-01

303

20S-dihydroprotopanaxatriol modulates functional activation of monocytes and macrophages  

PubMed Central

20S-dihydroprotopanaxatriol (2H-PPT) is a derivative of protopanaxatrol from ginseng. Unlike other components from Panax ginseng, the pharmacological activity of this compound has not been fully elucidated. In this study, we investigated the modulatory activity of 2H-PPT on the cellular responses of monocytes and macrophages to understand its immunoregulatory actions. 2H-PPT strongly upregulated the release of radicals in sodium nitroprusside-treated RAW264.7 cells and the surface levels of costimulatory molecule CD86. More importantly, this compound remarkably suppressed nitric oxide production, morphological changes, phagocytic uptake, cell-cell aggregation, and cell-matrix adhesion in RAW264.7 and U937 cells in the presence or absence of lipopolysaccharide, anti-CD43 antibody, fibronectin, and phorbal 12-myristate 13-acetate. Therefore, our results suggest that 2H-PPT can be applied as a novel functional immunoregulator of macrophages and monocytes. PMID:24198655

Kim, Mi-Yeon; Cho, Jae Youl

2013-01-01

304

Infection of human monocytes/macrophages by HIV-1: effect on secretion of IL-1 activity.  

PubMed Central

We have infected peripheral blood-derived monocyte/macrophage cultures with HIV-1 in order to determine the effect of such infection on cellular immunoregulatory function. We have confirmed that monocytes/macrophages are susceptible to infection by HIV-1, as determined by in situ hybridization using a HIV-1-specific RNA probe and by the presence of reverse transcriptase activity in culture supernatants. The cells employed efficiently supported viral replication in the absence of significant cytopathic effect, and secreted as little as 20% of the amount of IL-1 activity of uninfected controls in response to stimulation with either latex beads or lipopolysaccharide. This effect was not observed when UV-inactivated HIV-1 was used to infect the cells. Images Figure 1 PMID:3260578

Roy, S; Fitz-Gibbon, L; Poulin, L; Wainberg, M A

1988-01-01

305

YC-1 potentiates cAMP-induced CREB activation and nitric oxide production in alveolar macrophages  

SciTech Connect

Alveolar macrophages play significant roles in the pathogenesis of several inflammatory lung diseases. Increases in exhaled nitric oxide (NO) are well documented to reflect disease severity in the airway. In this study, we investigated the effect of 3-(5?-hydroxymethyl-2?-furyl)-1-benzyl indazole (YC-1), a known activator of soluble guanylyl cyclase, on prostaglandin (PG)E{sub 1} (a stable PGE{sub 2} analogue) and forskolin (a adenylate cyclase activator) induced NO production and inducible NO synthase (iNOS) expression in rat alveolar macrophages (NR8383). YC-1 did not directly cause NO production or iNOS expression, but drastically potentiated PGE{sub 1}- or forskolin-induced NO production and iNOS expression in NR8383 alveolar macrophages. Combination treatment with YC-1 and PGE{sub 1} significantly increased phosphorylation of the cAMP response element-binding protein (CREB), but not nuclear factor (NF)-?B activation. The combined effect on NO production, iNOS expression, and CREB phosphorylation was reversed by a protein kinase (PK)A inhibitor (H89), suggesting that the potentiating functions were mediated through a cAMP/PKA signaling pathway. Consistent with this, cAMP analogues, but not the cGMP analogue, caused NO release, iNOS expression, and CREB activation. YC-1 treatment induced an increase in PGE{sub 1}-induced cAMP formation, which occurred through the inhibition of cAMP-specific phosphodiesterase (PDE) activity. Furthermore, the combination of rolipram (an inhibitor of PDE4), but not milronone (an inhibitor of PDE3), and PGE{sub 1} also triggered NO production and iNOS expression. In summary, YC-1 potentiates PGE{sub 1}-induced NO production and iNOS expression in alveolar macrophages through inhibition of cAMP PDE activity and activation of the cAMP/PKA/CREB signaling pathway. Highlights: ? YC-1 potentiated PGE1-induced iNOS expression in alveolar macrophages. ? The combination of YC-1 and PGE1 increased CREB but not NF?B activation. ? The combined effects were reversed by H89. ? The combination of rolipram and PGE1 triggered NO production and iNOS expression. ? Effect of YC-1 occurred through inhibition of cAMP-specific PDE.

Hwang, Tsong-Long, E-mail: htl@mail.cgu.edu.tw [Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan (China) [Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan (China); Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Kweishan, Taoyuan, Taiwan (China); Tang, Ming-Chi [Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan (China)] [Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan (China); Kuo, Liang-Mou [Department of General Surgery, Chang Gung Memorial Hospital at Chia-Yi, Taiwan (China)] [Department of General Surgery, Chang Gung Memorial Hospital at Chia-Yi, Taiwan (China); Chang, Wen-De; Chung, Pei-Jen; Chang, Ya-Wen; Fang, Yao-Ching [Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan (China)] [Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan (China)

2012-04-15

306

Lipocalin 2 is a Regulator Of Macrophage Polarization and NF-?B/STAT3 Pathway Activation.  

PubMed

Lipocalin 2 (Lcn2) has been previously characterized as an adipokine/cytokine and implicated in obesity and inflammation. Herein, we investigated the role and potential mechanism of Lcn2 in the regulation of macrophage polarization in obesity-associated inflammation. We observed that Lcn2-/- mice displayed an up-regulation of expression of M1 macrophage marker Cd11c but a down-regulation of M2 marker arginase 1 in adipose tissue and liver of mice upon a high-fat diet feeding. Lcn2-deficient bone marrow-derived macrophages (BMDMs) were more sensitive to lipopolysaccharide (LPS) stimulation, leading to a more profound up-regulation of expression of pro-inflammatory markers than wild-type (WT) BMDMs. Accordingly, LPS stimulation elicited an increase in the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B), c-Jun, and STAT3 signaling pathways as well as an up-regualtion of expression of NF-?B and STAT3 target genes such as IL-1?, IL-6, iNOS, and MCP-1 in Lcn2-/- BMDMs compared with WT controls. Pre-treatment of recombinant Lcn2 attenuated LPS-stimulated degradation of I?B? and STAT3 phosphorylation as well as LPS-induced gene expression of IL-6 and iNOS in Lcn2-/- BMDMs. Moreover, the NF?B inhibitor markedly blocked LPS-stimulated STAT3 phosphorylation in Lcn2-/- BMDMs. These results together with the time course of Lcn2 secretion, NF?B and STAT3 phosphorylation in response to LPS stimulation, suggest that Lcn2 plays a role as an anti-inflammatory regulator in macrophage activation via modulating a feed-forward activation of NF?B-STAT3 loop. PMID:25127375

Guo, Hong; Jin, Daozhong; Chen, Xiaoli

2014-10-01

307

Vitamin D-binding protein contributes to COPD by activation of alveolar macrophages  

Microsoft Academic Search

BackgroundVitamin D-binding protein (DBP) genetic polymorphisms have been associated with chronic obstructive pulmonary disease (COPD). DBP has an indirect role in macrophage activation; thus it was hypothesised that DBP is present in the airway and contributes to lung disease by this mechanism.Methods471 PiZZ subjects with ?1-antitrypsin deficiency (AATD) were genotyped for tag single nucleotide polymorphisms (SNPs) covering the DBP gene

A M Wood; C Bassford; D Webster; P Newby; P Rajesh; R A Stockley; D R Thickett

2011-01-01

308

The Role of Progestogens in Regulating Matrix Metalloproteinase Activity in Macrophages and Microglial Cells  

Microsoft Academic Search

Although the systemic effects of progestogens have been extensively studied, little is known in regards to the cellular effects\\u000a of these compounds. Using a cellular model for vascular (macrophages) and brain (microglial) cells, we studied the effects\\u000a of various progestogens, either alone or in combination with 17?-estradiol (E2) on the activity of matrix metalloproteinase-9 (MMP-9), a proteolytic enzyme involved in

Juliana Hwang-LevineFrank; Frank Z. Stanczyk; Howard N. Hodis

309

Thioredoxin Peroxidase Secreted by Fasciola hepatica Induces the Alternative Activation of Macrophages  

Microsoft Academic Search

Received 13 April 2004\\/Returned for modification 23 May 2004\\/Accepted 25 August 2004 Alternatively activated macrophages (AAM) are primarily associated with the chronic stages of parasitic infections and the development of a polarized Th2 response. We have shown that Fasciola hepatica infection of BALB\\/c mice induces a polarized Th2 response during both the latent and chronic stage of disease. The acti-

Sheila Donnelly; Sandra M. O'Neill; Mary Sekiya; Grace Mulcahy; John P. Dalton

2005-01-01

310

Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes  

PubMed Central

Type 2 diabetes mellitus (T2DM) progresses from compensated insulin resistance to beta ceil failure resulting in uncompensated hyperglycemia, a process replicated in the Zucker diabetic fatty (ZDF) rat. The Nlrp3 inflammasome has been implicated in obesity-induced insulin resistance and beta cell failure. Endocannabinoids contribute to insuiin resistance through activation of peripheral CB1 receptors (CB1Rs) and also promote beta cell failure. Here we show that beta cell failure in adult ZDF rats is not associated with CB1R signaling in beta ceils, but rather in M1 macrophages infiltrating into pancreatic islets, and that this leads to activation of the Nlrp3-ASC inflammasome in the macrophages. These effects are replicated in vitro by incubating wild-type human or rodent macrophages, but not macrophages from CB1R-deficient [Cnr1?/?) or Nlrp3?/? mice, with the endocannabinoid anandamide. Peripheral CB1R blockade, in vivo depletion of macrophages or macrophage-specific knockdown of CB1R reverses or prevents these changes and restores normoglycemia and glucose-induced insulin secretion. These findings implicate endocannabinoids and inflammasome activation in beta cell failure and identify macrophage-expressed CB1R as a therapeutic target in T2DM. PMID:23955712

Jourdan, Tony; Godlewski, Grzegorz; Cinar, Resat; Bertola, Adeline; Szanda, Gergo; Liu, Jie; Tarn, Joseph; Han, Tiffany; Mukhopadhyay, Bani; Skarulis, Monica C; Ju, Cynthia; Aouadis, Myriam; Czech, Michael P; Kunos, George

2014-01-01

311

Immunomodulatory activity of the dimerized lysozyme KLP-602 after earlier suppression by atrazine in carp (Cyprinus carpio L.).  

PubMed

The purpose of this study was to determine the possibility of modulation of the cellular immune response with the dimer of lysozyme KLP-602 in fish after suppression induced by atrazine. In the in vivo studies fish were intoxicated with atrazine at a dose of 1/4 LD50, then after 48 hours the dimer of lysozyme KLP-602 was administerd at a dose of 0.02 mg/kg of body weight. After 2, 3, 5, 7 and 10 days after intoxication cells from the blood and pronephros of carp were isolated. In the study we determined the metabolic activity of phagocyte cells and the proliferative ability of T and B lymphocytes. This study showed that administration of the dimer of lysozyme KLP-602 stimulated and corrected the handicapped immunity. PMID:14509361

Rymuszka, A; Siwicki, A K

2003-01-01

312

Activation profile of dorsal root ganglia Iba-1 (+) macrophages varies with the type of lesion in rats.  

PubMed

The interactions between neurons, immune and immune-like glial cells can initiate the abnormal processes that underlie neuropathic pain. In the peripheral nervous system the resident macrophages may play an important role. In this study we investigated in experimental adult Sprague-Dawley rats how Iba-1 (ionized calcium binding adaptor molecule 1) (+) resident macrophages in the dorsal root ganglion (DRG) are activated after a spinal nerve ligation (SNL) or streptozotocin (STZ)-induced diabetes. The activation profile was defined by comparing the responses of resident macrophages against microglia in the spinal cord as they share a common origin. After SNL, the Iba-1 (+) macrophages in L5 DRG reached their activation peak 5 days later, clustered as satellite cells around large A-neurons, expressed the MHC-II marker, but did not show p-p38 and p-ERK1/2 activation and did not secrete IL-18. After STZ-induced diabetes, the Iba-1 (+) macrophages reached their activation peak 1 week later in L4 and L5 DRG, remained scattered between neurons, expressed the MHC-II marker only in L5 DRG, did not show p-p38 and p-ERK1/2 activation and did not secrete any of the investigated cytokines/chemokines. These responses suggest that depending on the type of lesion DRG Iba-1 (+) resident macrophages have different activation mechanisms, which are dissimilar to those in microglia. PMID:23701965

Ton, Bich-Hoai Thi; Chen, Qingmin; Gaina, Gisela; Tucureanu, Catalin; Georgescu, Adriana; Strungaru, Carmen; Flonta, Maria-Luiza; Sah, Dinah; Ristoiu, Violeta

2013-10-01

313

Macrophage activation and muscle remodeling at myotendinous junctions after modifications in muscle loading.  

PubMed Central

Modifications in muscle loading have been reported previously to result in increased numbers of mononucleated cells and changes in myofibril organization at myotendinous junctions (MTJs). The goals of this study were to determine the identity of those mononucleated cells and to examine the relationships between changes in their structure, location, and number with structural aspects of remodeling at MTJs experiencing modified loading. Soleus muscles from rats subjected to 10 days of hindlimb suspension were analyzed 0, 2, 4, and 7 days after return to weight bearing. Immunohistochemistry showed that ED1+, ED2+ and Ia+ macrophages were present at the MTJ and microtendon of control muscle. After reloading, ED2+ macrophages increased in number and size at MTJs and microtendons, indicating their activation. ED1+ cells showed no change in size or number whereas Ia+ cells were increased in size at day 7 of reloading. Electron microscopic observations showed that mononucleated cells near MTJs of control or suspended muscle were not highly active in protein synthesis or secretion. However, in reloaded muscle, mononucleated cells were found to be in close proximity to MTJs and to contain a high concentration of organelles associated with protein secretion. During these stages of reloading, extensive remodeling of myofibril-membrane associations occurred and nascent sarcomeres appeared in the MTJ regions of muscle fibers. Immunohistochemistry showed that during these stages of nascent sarcomere formation, there was renewed expression of developmental myosin heavy chain at MTJs, with this heavy chain appearing most prominently at the MTJ at day 7 of reloading. The activation and increased numbers of macrophages at MTJs and the close apposition of secretory cells to the MTJ membrane during remodeling lead us to propose that macrophage-derived factors may influence remodeling of MTJs in muscles experiencing modified loading. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 PMID:7992849

St Pierre, B. A.; Tidball, J. G.

1994-01-01

314

Immunomodulatory and Antibacterial Effects of Cystatin 9 against Francisella tularensis  

PubMed Central

Cystatin 9 (CST9) is a member of the type 2 cysteine protease inhibitor family, which has been shown to have immunomodulatory effects that restrain inflammation, but its functions against bacterial infections are unknown. Here, we report that purified human recombinant (r)CST9 protects against the deadly bacterium Francisella tularensis (Ft) in vitro and in vivo. Macrophages infected with the Ft human pathogen Schu 4 (S4), then given 50 pg of rCST9 exhibited significantly decreased intracellular bacterial replication and increased killing via preventing the escape of S4 from the phagosome. Further, rCST9 induced autophagy in macrophages via the regulation of the mammalian target of rapamycin (mTOR) signaling pathways. rCST9 promoted the upregulation of macrophage proteins involved in antiinflammation and antiapoptosis, while restraining proinflammatory-associated proteins. Interestingly, the viability and virulence of S4 also was decreased directly by rCST9. In a mouse model of Ft inhalation, rCST9 significantly decreased organ bacterial burden and improved survival, which was not accompanied by excessive cytokine secretion or subsequent immune cell migration. The current report is the first to show the immunomodulatory and antimicrobial functions of rCST9 against Ft. We hypothesize that the attenuation of inflammation by rCST9 may be exploited for therapeutic purposes during infection. PMID:23922243

Eaves-Pyles, Tonyia; Patel, Jignesh; Arigi, Emma; Cong, Yingzi; Cao, Anthony; Garg, Nisha; Dhiman, Monisha; Pyles, Richard B; Arulanandam, Bernard; Miller, Aaron L; Popov, Vsevolod L; Soong, Lynn; Carlsen, Eric D; Coletta, Ciro; Szabo, Csaba; Almeida, Igor C.

2013-01-01

315

Low molecular weight hyaluronan activates cytosolic phospholipase A2? and eicosanoid production in monocytes and macrophages.  

PubMed

Hyaluronan (HA) is the major glycosaminoglycan in the extracellular matrix. During inflammation, there is an increased breakdown of HA, resulting in the accumulation of low molecular weight (LMW) HA and activation of monocytes and macrophages. Eicosanoids, derived from the cytosolic phospholipase A2 group IVA (cPLA2?) activation, are potent lipid mediators also attributed to acute and chronic inflammation. The aim of this study was to determine the effect of LMW HA on cPLA2? activation, arachidonic acid (AA) release, and subsequent eicosanoid production and to examine the receptors and downstream mechanisms involved in these processes in monocytes and differently polarized macrophages. LMW HA was a potent stimulant of AA release in a time- and dose-dependent manner, induced cPLA2?, ERK1/2, p38, and JNK phosphorylation, as well as activated COX2 expression and prostaglandin (PG) E2 production in primary human monocytes, murine RAW 264.7, and wild-type bone marrow-derived macrophages. Specific cPLA2? inhibitor blocked HA-induced AA release and PGE2 production in all of these cells. Using CD44, TLR4, TLR2, MYD88, RHAMM or STAB2 siRNA-transfected macrophages and monocytes, we found that AA release, cPLA2?, ERK1/2, p38, and JNK phosphorylation, COX2 expression, and PGE2 production were activated by LMW HA through a TLR4/MYD88 pathway. Likewise, PGE2 production and COX2 expression were blocked in Tlr4(-/-) and Myd88(-/-) mice, but not in Cd44(-/-) mice, after LMW HA stimulation. Moreover, we demonstrated that LMW HA activated the M1 macrophage phenotype with the unique cPLA2?/COX2(high) and COX1/ALOX15/ALOX5/LTA4H(low) gene and PGE2/PGD2/15-HETE(high) and LXA4(low) eicosanoid profile. These findings reveal a novel link between HA-mediated inflammation and lipid metabolism. PMID:24366870

Sokolowska, Milena; Chen, Li-Yuan; Eberlein, Michael; Martinez-Anton, Asuncion; Liu, Yueqin; Alsaaty, Sara; Qi, Hai-Yan; Logun, Carolea; Horton, Maureen; Shelhamer, James H

2014-02-14

316

Identification of a Denitrase Activity Against Calmodulin in Activated Macrophages Using High-Field Liquid Chromatography - FTICR Mass Spectrometry  

SciTech Connect

We have identified a denitrase activity in macrophages that is upregulated following macrophage activation, which is shown by mass spectrometry to recognize nitrotyrosines in the calcium signaling protein calmodulin (CaM) and convert them to their native tyrosine structure without the formation of any aminotyrosine. Comparable extents of methionine sulfoxide reduction are also observed that are catalyzed by endogenous methionine sulfoxide reductases. Competing with repair processes, oxidized CaM is a substrate for a peptidase activity that results in the selective cleavage of the C-terminus lysine (i.e., Lys148) that is expected to diminish CaM function. Thus, competing repair and peptidase activities define the abundances and functionality of CaM to modulate cellular metabolism in response to oxidative stress, where the presence of the truncated CaM species provides a useful biomarker for the transient appearance of oxidized CaM.

Smallwood, Heather S.; Lourette, Natacha M.; Boschek, Curt B.; Bigelow, Diana J.; Smith, Richard D.; Pasa-Tolic, Liljiana; Squier, Thomas C.

2007-09-18

317

Thalidomide treatment modulates macrophage pro-inflammatory function and cytokine levels in Klebsiella pneumoniae B5055 induced pneumonia in BALB\\/c mice  

Microsoft Academic Search

Lung innate immune response plays an important role in the clearance of pathogens from lungs, however, profound activation of innate immune cells (alveolar macrophages or neutrophils) can lead to development of acute lung inflammation or injury by producing various pro-inflammatory molecules (IL-1, TNF-? and H2O2 etc.). Present study is designed to investigate the immunomodulatory action of thalidomide in Klebsiella pneumoniae

Vijay Kumar; Kusum Harjai; Sanjay Chhibber

2010-01-01

318

Alveolar macrophage function in rats with severe protein calorie malnutrition. Arachidonic acid metabolism, cytokine release, and antimicrobial activity.  

PubMed

To investigate the effects of protein calorie malnutrition (PCM) on alveolar macrophage function, we measured antimicrobial activity, IL-1 and TNF production, and arachidonic acid metabolism in alveolar macrophages of infant rats with moderate and severe PCM. Groups of weanling male rats were fed a diet containing 0.8% protein (PCM) or 24% protein (control). A third group (pair fed) was fed limited amounts of the control diet that matched the mean daily dietary intake of the PCM group. After 4 wk on the diets, alveolar macrophages from all three groups functioned similarly with respect to surface adherence, phagocytosis and killing of Listeria monocytogenes, release of hydrogen peroxide and superoxide anion, and production of IL-1 and TNF. In contrast, Listeria-stimulated alveolar macrophages from the PCM group exhibited a marked shift in arachidonic acid metabolism, with impaired production of leukotriene B4 and enhanced release of thromboxane B2 and PGE2. The membrane arachidonic acid content and the uptake of [3H]arachidonate by alveolar macrophages did not differ among the three groups. The shift toward the cyclooxygenase pathway was not seen after 2 wk of dietary restriction and was reversed if PCM animals were fed the control diet for 1 wk. Thus, PCM does not affect the antimicrobial activity or cytokine production of alveolar macrophages, but causes alterations in arachidonic acid metabolism that may interfere with the modulatory functions of alveolar macrophages. PMID:2104909

Skerrett, S J; Henderson, W R; Martin, T R

1990-02-01

319

Phagocytosis-induced 51Cr release from activated macrophages and blood mononuclears. Effect of colchicine and antioxidants  

SciTech Connect

The chromium-release test was adapted to the measurement of the cellular injury induced when activated macrophages phagocytose particulates. Macrophages obtained from rabbit lungs undergoing BCG-induced chronic inflammation released more chromium when incubated in the presence of phagocytosable particles than when incubated under resting conditions. Blood mononuclear cells, 40-60% monocytes, procured from the same BCG-injected animals, were less susceptible to phagocytosis-induced injury than the macrophages obtained from the lungs. The amount of chromium released by the activated macrophages was proportional to the number of particles present during incubation. In the presence of catalase, the amounts of chromium released by phagocytosing and resting macrophages were similar; in the presence of superoxide dismutase and cytochrome c, the amount of chromium released by phagocytosing macrophages was 13-35% less than the amount of chromium released by macrophages incubated without the antioxidants. In addition, colchicine, an inhibitor of degranulation also exerted partial inhibition of the chromium release. These results suggest that oxygen radicals and lysosomal contents contribute to the cellular injury that results from phagocytosis.

McGee, M.P.; Hale, A.H.

1981-09-01

320

Evidence for a prosurvival role of alpha-7 nicotinic acetylcholine receptor in alternatively (M2)-activated macrophages  

PubMed Central

Abstract Recent observations in endothelial cells and macrophages indicate that nicotinic acetylcholine receptors (nAChRs) are potential novel players in mechanisms linked to atherogenesis. In macrophages, ?7nAChR mediates anti?inflammatory actions and contributes to regulation of cholesterol flux and phagocytosis. Considering that macrophage apoptosis is a key process throughout all stages of atherosclerotic lesion development, in the present study, we examined for the first time the impact of ?7nAChR expression and function in macrophage survival and apoptosis using in vitro polarized (M1 and M2) bone marrow?derived macrophages (BMDMs) from wild?type and ?7nAChR knockout mice. Our findings show that stimulation of ?7nAChR results in activation of the STAT3 prosurvival pathway and protection of macrophages from endoplasmic reticulum (ER) stress?induced apoptosis. These actions are rather selective for M2 BMDMs and are associated to activation of the JAK2/STAT3 axis. Remarkably, these effects are completely lost in M2 macrophages lacking ?7nAChR. PMID:24744866

Lee, Robert H.; Vazquez, Guillermo

2013-01-01

321

Effects of cigarette smoke on Toll-like receptor (TLR) activation of chronic obstructive pulmonary disease (COPD) macrophages.  

PubMed

Chronic obstructive pulmonary disease (COPD) is characterized by an abnormal innate immune response. We have investigated the changes in the innate immune response of COPD alveolar macrophages exposed to both cigarette smoke and Toll-like receptor (TLR) stimulation. COPD and control alveolar macrophages were exposed to cigarette smoke extract (CSE) followed by TLR-2, -4 and -5 ligands [Pam3CSK4, lipopolysaccharide (LPS) and phase I flagellin (FliC), respectively] or non-typeable Haemophilus influenzae (NTHi). CSE exposure suppressed TLR-induced tumour necrosis factor (TNF)-?, interleukin (IL)-6, IL-10 and regulated on activation, normal T cell expressed and secreted (RANTES) production in both COPD and control alveolar macrophages, but had no effect on interleukin 8 (CXCL8) production. Similarly, CSE suppressed NTHi-induced TNF-? but not NTHi-induced CXCL8 production in COPD alveolar macrophages. Gene expression analysis showed that CSE suppressed LPS-induced TNF-? transcription but not CXCL8 transcription in COPD alveolar macrophages. The dampening effect of CSE on LPS-induced cytokine production was associated with a reduction in p38, extracellular signal regulated kinase (ERK) and p65 activation. In conclusion, CSE caused a reduced innate immune response in COPD alveolar macrophages, with the exception of persistent CXCL8 production. This could be a mechanism by which alveolar macrophages promote neutrophil chemotaxis under conditions of oxidative stress and bacterial exposure. PMID:24528166

Metcalfe, H J; Lea, S; Hughes, D; Khalaf, R; Abbott-Banner, K; Singh, D

2014-06-01

322

Effects of polysaccharides from different species of Dendrobium (Shihu) on macrophage function.  

PubMed

Dendrobium spp. are precious medicinal plants, used in China for thousands of years as health foods and nutrients. Polysaccharides are the main effective ingredients in Dendrobium plants. In this study, the chemical characteristics and the effects of crude polysaccharides (CPs) from five species of Dendrobium on macrophage function were investigated and compared in vitro for the first time. Chemical characteristic studies showed that CPs from different species of Dendrobium were diverse, displaying widely varied Mw distributions and molar ratios of monosaccharides. Their effects on macrophage functions, such as promoting phagocytosis, release of NO and cytokines IL-1?, IL-6, IL-10 and TNF-?, were also different. Moreover, CPs from D. officinale, especially collected from Yunnan Province, exerted the strongest immunomodulatory activities and could be explored as a novel potential functional food. The diverse chemical characteristics of CPs from different species of Dendrobium might contribute to their varied effects on macrophage functions, which should be further investigated. PMID:23685935

Meng, Lan-Zhen; Lv, Guang-Ping; Hu, De-Jun; Cheong, Kit-Leong; Xie, Jing; Zhao, Jing; Li, Shao-Ping

2013-01-01

323

Activated macrophages down-regulate expression of E-cadherin in hepatocellular carcinoma cells via NF-?B/Slug pathway.  

PubMed

Hepatocellular carcinomas are an aggressive malignancy mainly due to metastasis or postsurgical recurrence. Expression of E-cadherin is strongly reduced in Hepatocellular carcinoma (HCC) tissues, and its downregulation is connected to invasiveness and metastasis in hepatocellular carcinomas. The previous study showed that the supernatant from activated macrophages can downregulate the expression of E-cadherin in HCC cells. The partial known molecular mechanism is that tyrosine kinases c-Src- and EGFR phosphorylate ?-catenin and E-cadherin leading to destabilization of E-cadherin/?-catenin complex. The aim of this study is to clarify other mechanism by which activated macrophages downregulate the expression of E-cadherin. We detect the expression of E-cadherin and macrophage infiltration in hepatocellular carcinoma tissues by double-staining immunohistochemistry and evaluate the relationship between macrophages and E-cadherin expression in hepatocellular carcinoma cells in vitro experiments. We found that reduced expression of E-cadherin was associated with macrophage infiltration along the border between the tumor nest and stroma in hepatocellular carcinoma tissues. Besides, protein expression of E-cadherin was significantly decreased in hepatocellular carcinoma cells co-cultured with macrophages derived from THP-1 cells. Consistently, mRNA expression of E-cadherin was also decreased in cancer cells co-cultured with THP-1-differentiated macrophages. Moreover, the downregulation of E-cadherin expression was companied by upregulation of Slug expression in cancer cells with conditional medium from THP-1-differentiated macrophage culture. The change in expression of E-cadherin and Slug was abrogated when NF-?B signaling pathway was blocked. All the findings suggested that macrophages contributed to the decreased expression of E-cadherin by NF-?B/Slug pathway in hepatocellular carcinomas. PMID:24894673

Wang, Xianteng; Wang, Hao; Li, Guosheng; Song, Yonghong; Wang, Shurong; Zhu, Faliang; Guo, Chun; Zhang, Lining; Shi, Yongyu

2014-09-01

324

Primary alveolar macrophages exposed to diesel particulate matter increase RAGE expression and activate RAGE signaling.  

PubMed

Receptors for advanced glycation end-products (RAGE) are members of the immunoglobulin superfamily of cell-surface receptors implicated in mechanisms of pulmonary inflammation. In the current study, we test the hypothesis that RAGE mediates inflammation in primary alveolar macrophages (AMs) exposed to diesel particulate matter (DPM). Quantitative RT-PCR and immunoblotting revealed that RAGE was up-regulated in Raw264.7 cells, an immortalized murine macrophage cell line and primary AMs exposed to DPM for 2 h. Because DPM increased RAGE expression, we exposed Raw264.7 cells and primary AMs isolated from RAGE null and wild-type (WT) mice to DPM prior to the assessment of inflammatory signaling intermediates. DPM led to the activation of Rat sarcoma GTPase (Ras), p38 MAPK and NF-?B in WT AMs and, when compared to WT AMs, these intermediates were diminished in DPM-exposed AMs isolated from RAGE null mice. Furthermore, cytokines implicated in inflammation, including IL-4, IL-12, IL-13 and TNF?, were all significantly decreased in DPM-exposed RAGE null AMs compared to similarly exposed WT AMs. These results demonstrate that diesel-induced inflammatory responses by primary AMs are mediated, at least in part, via RAGE signaling mechanisms. Further work may show that RAGE signaling in both alveolar epithelial cells and resident macrophages is a potential target in the treatment of inflammatory lung diseases exacerbated by environmental pollution. PMID:24859220

Barton, David B; Betteridge, Bryce C; Earley, Tyler D; Curtis, Cameron S; Robinson, Adam B; Reynolds, Paul R

2014-10-01

325

Mycobacterium's Arrest of Phagosome Maturation in Macrophages Requires Rab5 Activity and Accessibility to Iron  

PubMed Central

Many mycobacteria are intramacrophage pathogens that reside within nonacidified phagosomes that fuse with early endosomes but do not mature to phagolysosomes. The mechanism by which mycobacteria block this maturation process remains elusive. To gain insight into whether fusion with early endosomes is required for mycobacteria-mediated inhibition of phagosome maturation, we investigated how perturbing the GTPase cycles of Rab5 and Rab7, GTPases that regulate early and late endosome fusion, respectively, would affect phagosome maturation. Retroviral transduction of the constitutively activated forms of both GTPases into primary murine macrophages had no effect on Mycobacterium avium retention in an early endosomal compartment. Interestingly, expression of dominant negative Rab5, Rab5(S34N), but not dominant negative Rab7, resulted in a significant increase in colocalization of M. avium with markers of late endosomes/lysosomes and increased mycobacterial killing. This colocalization was specific to mycobacteria since Rab5(S34N) expressing cells showed diminished trafficking of endocytic tracers to lysosomes. We further demonstrated that maturation of M. avium phagosomes was halted in Rab5(S34N) expressing macrophages supplemented with exogenous iron. These findings suggest that fusion with early endosomes is required for mycobacterial retention in early phagosomal compartments and that an inadequate supply of iron is one factor in mycobacteria's inability to prevent the normal maturation process in Rab5(S34N)-expressing macrophages. PMID:12925769

Kelley, Victoria A.; Schorey, Jeffrey S.

2003-01-01

326

Pneumolysin Activates Macrophage Lysosomal Membrane Permeabilization and Executes Apoptosis by Distinct Mechanisms without Membrane Pore Formation  

PubMed Central

ABSTRACT Intracellular killing of Streptococcus pneumoniae is complemented by induction of macrophage apoptosis. Here, we show that the toxin pneumolysin (PLY) contributes both to lysosomal/phagolysosomal membrane permeabilization (LMP), an upstream event programing susceptibility to apoptosis, and to apoptosis execution via a mitochondrial pathway, through distinct mechanisms. PLY is necessary but not sufficient for the maximal induction of LMP and apoptosis. PLY’s ability to induce both LMP and apoptosis is independent of its ability to form cytolytic pores and requires only the first three domains of PLY. LMP involves TLR (Toll-like receptor) but not NLRP3/ASC (nucleotide-binding oligomerization domain [Nod]-like receptor family, pyrin domain-containing protein 3/apoptosis-associated speck-like protein containing a caspase recruitment domain) signaling and is part of a PLY-dependent but phagocytosis-independent host response that includes the production of cytokines, including interleukin-1 beta (IL-1?). LMP involves progressive and selective permeability to 40-kDa but not to 250-kDa fluorescein isothiocyanate (FITC)-labeled dextran, as PLY accumulates in the cytoplasm. In contrast, the PLY-dependent execution of apoptosis requires phagocytosis and is part of a host response to intracellular bacteria that also includes NO generation. In cells challenged with PLY-deficient bacteria, reconstitution of LMP using the lysomotrophic detergent LeuLeuOMe favored cell necrosis whereas PLY reconstituted apoptosis. The results suggest that PLY contributes to macrophage activation and cytokine production but also engages LMP. Following bacterial phagocytosis, PLY triggers apoptosis and prevents macrophage necrosis as a component of a broad-based antimicrobial strategy. This illustrates how a key virulence factor can become the focus of a multilayered and coordinated innate response by macrophages, optimizing pathogen clearance and limiting inflammation. PMID:25293758

Bewley, Martin A.; Naughton, Michael; Preston, Julie; Mitchell, Andrea; Holmes, Ashleigh; Marriott, Helen M.; Read, Robert C.; Mitchell, Timothy J.; Whyte, Moira K. B.

2014-01-01

327

Macrophages activated by fibrin increase albumin permeability across pulmonary artery endothelial monolayers  

SciTech Connect

We have examined the effects of alveolar macrophages (AM) obtained after challenge with alpha-thrombin on 125I-labeled albumin permeability across ovine pulmonary artery endothelial monolayers. AM were obtained by bronchoalveolar lavage before and after challenging the sheep with alpha-thrombin (80 U/kg). Post-thrombin AM increased 125I-labeled albumin transendothelial permeability, whereas resting AM had no effect (82.7 +/- 7.9% increase versus 17.2 +/- 1.6% increase at the AM:endothelial cell ratio of 1:1; p less than 0.001). The permeability increase was also seen at AM:endothelial cell ratios of 0.2:1 and 5:1. Endothelial permeability to 125I-labeled albumin did not increase after in vitro incubation of macrophages with 10(-8) M thrombin, suggesting that AM are activated as a result of thrombin-induced fibrin microembolism rather than by the alpha-thrombin per se. The increase in permeability was not due to endothelial lysis since macrophages did not cause release of endothelial lactate dehydrogenase. Adherence of AM to the endothelium did not correlate with the ability of AM to increase endothelial permeability. Superoxide anion production was increased when post-thrombin AM were exposed to the endothelial monolayers (30.6 +/- 4.2 nmol/10(6) cells/10 min) compared with production by post-thrombin AM in the absence of endothelial cells (2.5 +/- 0.5 nmol/10(6) cells/10 min). The addition of superoxide dismutase (SOD) blunted the permeability increase induced by AM (32.3 +/- 3.9% increase with SOD versus 84.1 +/- 7.1% increase without SOD; p less than 0.001), indicating that superoxide anion is an important mediator of the macrophage-induced increase in endothelial monolayer permeability.

Ferro, T.J.; Lynch, J.J.; Malik, A.B.

1989-04-01

328

The Small Ubiquitin-like Modifier-Deconjugating Enzyme Sentrin-Specific Peptidase 1 Switches IFN Regulatory Factor 8 from a Repressor to an Activator during Macrophage Activation  

PubMed Central

Macrophages, when activated by IFN-? and TLR signaling, elicit innate immune responses. IFN regulatory factor 8 (IRF8) is a transcription factor that facilitates macrophage activation and innate immunity. We show that, in resting macrophages, some IRF8 is conjugated to small ubiquitin-like modifiers (SUMO) 2/3 through the lysine residue 310. SUMO3-conjugated IRF8 failed to induce IL12p40 and other IRF8 target genes, consistent with SUMO-mediated transcriptional repression reported for other transcription factors. SUMO3-conjugated IRF8 showed reduced mobility in live nuclei and bound poorly to the IL12p40 gene. However, macrophage activation caused a sharp reduction in the amount of SUMOylated IRF8. This reduction coincided with the induction of a deSUMOylating enzyme, sentrin-specific peptidase 1 (SENP1), in activated macrophages. In transfection analysis, SENP1 removed SUMO3 from IRF8 and enhanced expression of IL12p40 and other target genes. Conversely, SENP1 knockdown repressed IRF8 target gene expression. In parallel with IRF8 deSUMOylation, macrophage activation led to the induction of proteins active in the SUMO pathway and caused a global shift in nuclear protein SUMOylation patterns. Together, the IRF8 SUMO conjugation/deconjugation switch is part of a larger transition in SUMO modifications that takes place upon macrophage activation, serving as a mechanism to trigger innate immune responses. PMID:22942423

Chang, Tsung-Hsien; Xu, Songxiao; Tailor, Prafullakumar; Kanno, Tomohiko; Ozato, Keiko

2014-01-01

329

Transcriptional activation of the lipoprotein lipase and apolipoprotein E genes accompanies differentiation in some human macrophage-like cell lines  

Microsoft Academic Search

Stimulation of the macrophage-like cell line THP-1 with the phorbol ester phorbol 12-myristate 13-acetate (PMA) resulted in differentiation into cells with many features of macrophages. This differentiation was accompanied by transcriptional activation of the lipoprotein lipase (LPL) and apo E genes and accumulation of their protein products in the media. PMA-induced differentiation of the HEL and HL-60 cell lines was

Johan H. Auwerx; Samir Deeb; John D. Brunzell; Reiling Peng; Alan Chait

1988-01-01

330

Macrophage phenotypes in atherosclerosis.  

PubMed

Initiation and progression of atherosclerosis depend on local inflammation and accumulation of lipids in the vascular wall. Although many cells are involved in the development and progression of atherosclerosis, macrophages are fundamental contributors. For nearly a decade, the phenotypic heterogeneity and plasticity of macrophages has been studied. In atherosclerotic lesions, macrophages are submitted to a large variety of micro-environmental signals, such as oxidized lipids and cytokines, which influence the phenotypic polarization and activation of macrophages resulting in a dynamic plasticity. The macrophage phenotype spectrum is characterized, at the extremes, by the classical M1 macrophages induced by T-helper 1 (Th-1) cytokines and by the alternative M2 macrophages induced by Th-2 cytokines. M2 macrophages can be further classified into M2a, M2b, M2c, and M2d subtypes. More recently, additional plaque-specific macrophage phenotypes have been identified, termed as Mox, Mhem, and M4. Understanding the mechanisms and functional consequences of the phenotypic heterogeneity of macrophages will contribute to determine their potential role in lesion development and plaque stability. Furthermore, research on macrophage plasticity could lead to novel therapeutic approaches to counteract cardiovascular diseases such as atherosclerosis. The present review summarizes our current knowledge on macrophage subsets in atherosclerotic plaques and mechanism behind the modulation of the macrophage phenotype. PMID:25319333

Colin, Sophie; Chinetti-Gbaguidi, Giulia; Staels, Bart

2014-11-01

331

Toll-like receptor activation of XBP1 regulates innate immune responses in macrophages  

PubMed Central

Sensors of pathogens, such as Toll-like receptors (TLRs), detect microbes to activate transcriptional programs that orchestrate adaptive responses to specific insults. Here we report that TLR4 and TLR2 specifically activated the endoplasmic reticulum (ER)-stress sensor kinase IRE1? and its downstream target, the transcription factor XBP1. Previously described XBP1 ER stress target genes were not induced by TLR signaling. Instead, TLR-activated XBP1 was required for optimal and sustained production of proinflammatory cytokines in macrophages. Consistent with this finding, IRE1? activation by ER-stress synergized with TLR activation for cytokine production. Moreover, XBP1 deficiency markedly increased bacterial burden in animals infected with the TLR2-activating human pathogen Francisella tularensis. Our findings uncover an unsuspected critical new function for the XBP1 transcription factor in mammalian host defenses. PMID:20351694

Martinon, Fabio; Chen, Xi; Lee, Ann-Hwee; Glimcher, Laurie H.

2011-01-01

332

Nitroglycerin Alters Matrix Remodeling Proteins in THP-1 Human Macrophages and Plasma Metalloproteinase Activity in Rats  

PubMed Central

Several studies suggested that long-term nitrate therapy may produce negative outcomes in patient mortality and morbidity. A possible mechanism may involve nitrate-mediated activation of various extracellular matrix (ECM) proteases, particularly matrix metalloproteinase-9 (MMP-9), and adhesion molecules in human macrophages, leading to the destabilization of atherosclerotic plaques. We examined the gene and protein regulating effects on THP-1 human macrophages by repeated exposure to therapeutically relevant concentrations of nitroglycerin (NTG) and possible involvement of nuclear factor (NF)-?B signaling mechanism in mediating some of these observed effects. THP-1 human macrophages repeatedly exposed to NTG (at 10 nM, added on days 1, 4 and 7) exhibited extensive alterations in the expression of multiple genes encoding ECM proteases and adhesion molecules. These effects were dissimilar to those produced by a direct nitric oxide donor, diethylenetriamine NONOate. NTG exposure significantly up-regulated NF-?B DNA nuclear binding activity and MMP-9 protein expression, and reduced tissue inhibitor of metalloproteinase-1 (TIMP-1) expression; these effects were abrogated in the presence of the NF-?B inhibitor parthenolide (a chemical inhibitor derived from the feverfew plant). Further, we examined whether our in vitro findings (an elevated MMP-9/TIMP-1 ratio and gelatinase activity) can be translated to in vivo effects, in a rat model. Sprague-Dawley rats exposed continuously to NTG subcutaneously for 8 days via mini-osmotic pumps showed significant induction of plasma MMP-9 dimer concentrations and the expression of a complex of MMP-9 with lipocalin-2 or neutrophil gelatinase associated lipocalin (NGAL). Plasma gelatinase activity was significantly increased by NTG over the entire study period, attaining peak elevation at day 6. Plasma TIMP-1 protein was down-regulated significantly by day 2 and days 4 to 7 in the NTG-treated rats. Pharmacokinetic monitoring of NTG and its dinitrate metabolites indicated that concentrations were well within therapeutic levels observed in humans. Our studies indicate that clinically relevant concentrations of NTG not only altered ECM matrix by changing the expression of multiple genes that govern cellular integrity, affecting cellular MMP-9/TIMP-1 balance in THP-1 human macrophages possibly via NF-?B activation, but also led to systemic changes in MMP-9/TIMP-1 expression and gelatinase activity in rats. These effects may contribute to extracellular matrix degradation and possible atherosclerotic plaque destabilization. PMID:21156214

Krishnatry, Anu Shilpa; Fung, Sun Mi; Brazeau, Daniel A.; Soda, David; Fung, Ho-Leung

2010-01-01

333

FXR agonist GW4064 alleviates endotoxin-induced hepatic inflammation by repressing macrophage activation  

PubMed Central

AIM: To examine the effect of farnesoid X receptor (FXR) activation by GW4064 on endotoxin-induced hepatic inflammation in nonalcoholic fatty liver disease (NAFLD) and the underlying mechanism. METHODS: Six-week-old male C57BL/6 mice were fed a normal diet or a high-fat (HF) diet for 8 wk. HF diet-fed mice were intraperitoneally injected with GW4064 (30 mg/kg) or DMSO (vehicle) once daily for a week and then sacrificed after lipopolysaccharide (LPS, 50 ?g/mouse) administration. Hepatic inflammation, levels of the macrophage marker F4/80, and apoptosis were measured at the end of the study. Additionally, the expression of proinflammatory genes involved in NAFLD (interleukin-6, interleukin-1?, interferon-?, MCP-1) were analyzed by real-time PCR in the murine macrophage cell line RAW 264.7 cultured with or without GW4064 (2 ?mol/L) before treatment with LPS. RESULTS: In patients with NAFLD, the expression of FXR was detected by immunohistochemical staining and the relation between FXR expression and NAFLD activity score (NAS) was analyzed. Activation of FXR by GW4064 alleviated hepatic inflammation induced by endotoxin in a murine NAFLD model fed an HF diet as reflected by reduced serum levels of aspartate aminotransferase and alanine aminotransferase. Apoptosis and proinflammatory cytokine levels in liver tissues were also reduced by GW4064, and GW4064 could reduce induction of proinflammatory cytokines by LPS in vitro. FXR levels were reduced in patients with non-alcoholic steatohepatitis compared with healthy controls and were negatively correlated with NAS. CONCLUSION: FXR activation attenuates LPS-induced hepatic inflammation in murine NAFLD by reducing expression of proinflammatory cytokines in macrophages. PMID:25339829

Yao, Jun; Zhou, Chun-Suo; Ma, Xiong; Fu, Bai-Qing; Tao, Li-Sheng; Chen, Miao; Xu, Ya-Ping

2014-01-01

334

Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages.  

PubMed

Macrophages acquire strikingly different properties that enable them to play key roles during the initiation, propagation, and resolution of inflammation. Classically activated (M1) macrophages produce proinflammatory mediators to combat invading pathogens and respond to tissue damage in the host, whereas regulatory macrophages (M2b) produce high levels of anti-inflammatory molecules, such as IL-10, and low levels of proinflammatory cytokines, like IL-12, and are important for the resolution of inflammatory responses. A central problem in this area is to understand how the formation of regulatory macrophages can be promoted at sites of inflammation to prevent and/or alleviate chronic inflammatory and autoimmune diseases. Here, we demonstrate that the salt-inducible kinases (SIKs) restrict the formation of regulatory macrophages and that their inhibition induces striking increases in many of the characteristic markers of regulatory macrophages, greatly stimulating the production of IL-10 and other anti-inflammatory molecules. We show that SIK inhibitors elevate IL-10 production by inducing the dephosphorylation of cAMP response element-binding protein (CREB)-regulated transcriptional coactivator (CRTC) 3, its dissociation from 14-3-3 proteins and its translocation to the nucleus where it enhances a gene transcription program controlled by CREB. Importantly, the effects of SIK inhibitors on IL-10 production are lost in macrophages that express a drug-resistant mutant of SIK2. These findings identify SIKs as a key molecular switch whose inhibition reprograms macrophages to an anti-inflammatory phenotype. The remarkable effects of SIK inhibitors on macrophage function suggest that drugs that target these protein kinases may have therapeutic potential for the treatment of inflammatory and autoimmune diseases. PMID:23033494

Clark, Kristopher; MacKenzie, Kirsty F; Petkevicius, Kasparas; Kristariyanto, Yosua; Zhang, Jiazhen; Choi, Hwan Geun; Peggie, Mark; Plater, Lorna; Pedrioli, Patrick G A; McIver, Ed; Gray, Nathanael S; Arthur, J Simon C; Cohen, Philip

2012-10-16

335

The Orosomucoid 1 protein is involved in the vitamin D – mediated macrophage de-activation process  

SciTech Connect

Orosomucoid 1 (ORM1), also named Alpha 1 acid glycoprotein A (AGP-A), is an abundant plasma protein characterized by anti-inflammatory and immune-modulating properties. The present study was designed to identify a possible correlation between ORM1 and Vitamin D3 (1,25(OH)2D3), a hormone exerting a widespread effect on cell proliferation, differentiation and regulation of the immune system. In particular, the data described here indicated that ORM1 is a 1,25(OH)2D3 primary response gene, characterized by the presence of a VDRE element inside the 1 kb sequence of its proximal promoter region. This finding was demonstrated with gene expression studies, Chromatin Immunoprecipitation and luciferase transactivation experiments and confirmed by VDR full length and dominant negative over-expression. In addition, several experiments carried out in human normal monocytes demonstrated that the 1,25(OH)2D3 – VDR – ORM1 pathway plays a functional role inside the macrophage de-activation process and that ORM1 may be considered as a signaling molecule involved in the maintenance of tissue homeostasis and remodeling. - Highlights: • ORM1 is a Vitamin D primary response gene. • VD and its receptor VDR are involved in the de-activation process mediated by human resident macrophages. • The signaling pathway VD-VDR-ORM1 plays an important role in the control of macrophage de-activation process. • ORM1 may be defined as a signaling molecule implicated in the maintenance of tissue homeostasis and remodeling.

Gemelli, Claudia, E-mail: claudia.gemelli@unimore.it [Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena (Italy); Center for Regenerative Medicine, University of Modena and Reggio Emilia, Via Gottardi 100, 41125 Modena (Italy); Martello, Andrea; Montanari, Monica; Zanocco Marani, Tommaso; Salsi, Valentina; Zappavigna, Vincenzo; Parenti, Sandra; Vignudelli, Tatiana; Selmi, Tommaso; Ferrari, Sergio; Grande, Alexis [Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena (Italy)

2013-12-10

336

Growth of ovine granulocyte-macrophage precursors in vitro without exogenous colony-stimulating activity  

SciTech Connect

Ovine granulocyte-macrophage colony-forming units (CFU-GM) from peripheral blood and bone marrow were cultured in vitro. The colony-stimulating activity (CSA) was provided by various conditioned-media previously reported to contain CSA and by homologous sheep serum (SS). The maximum number of CFU-GM was observed in the cultures containing SS without the addition of exogenous CSA. The CFU-GM appeared earlier in the cultures containing bone marrow cells when compared to the peripheral blood CFU-GM. Replacement of SS by bovine fetal serum resulted in suboptimal growth of ovine CFU-GM.

Chandra, P.; Joel, D.D.; Chanana, A.D.

1983-11-01

337

Intracellular activity of tedizolid phosphate and ACH-702 versus Mycobacterium tuberculosis infected macrophages  

PubMed Central

Background Due to the emergency of multidrug-resistant strains of Mycobacterium tuberculosis, is necessary the evaluation of new compounds. Findings Tedizolid, a novel oxazolidinone, and ACH-702, a new isothiazoloquinolone, were tested against M. tuberculosis infected THP-1 macrophages. These two compounds significantly decreased the number of intracellular mycobacteria at 0.25X, 1X, 4X and 16X the MIC value. The drugs were tested either in nanoparticules or in free solution. Conclusion Tedizolid and ACH-702 have a good intracellular killing activity comparable to that of rifampin or moxifloxacin. PMID:24708819

2014-01-01

338

Inhibition of Inflammatory Response by Artepillin C in Activated RAW264.7 Macrophages.  

PubMed

Artepillin C (3,5-diprenyl-4-hydroxycinnamic acid) is the main bioactive component of Brazilian green propolis. The aim of this study was to investigate the anti-inflammatory effect of artepillin C on LPS + IFN- ? - or PMA-stimulated RAW264.7 macrophages. The cell viability was evaluated by MTT and LDH assays. The radical scavenging ability was determined using DPPH(•) and ABTS(•+). ROS and RNS generation was analyzed by chemiluminescence. NO concentration was detected by the Griess reaction. The release of various cytokines by activated RAW264.7 cells was measured in the culture supernatants using a multiplex bead array system based on xMAP technology. NF- ? B activity was confirmed by the ELISA-based TransAM NF- ? B kit. At the tested concentrations, the compound did not decrease the cell viability and did not cause the cytotoxicity. Artepillin C exerted strong antioxidant activity, significantly inhibited the production of ROS, RNS, NO, and cytokine IL-1 ? , IL-3, IL-4, IL-5, IL-9, IL-12p40, IL-13, IL-17, TNF- ? , G-CSF, GM-CSF, MCP-1, MIP-1 ? , MIP-1 ? , RANTES, and KC, and markedly blocked NF- ? B expression in stimulated RAW264.7 macrophages. Our findings provide new insights for understanding the mechanism involved in the anti-inflammatory effect of artepillin C and support the application of Brazilian green propolis in complementary and alternative medicine. PMID:23781267

Szliszka, Ewelina; Mertas, Anna; Czuba, Zenon P; Król, Wojciech

2013-01-01

339

Inhibition of Inflammatory Response by Artepillin C in Activated RAW264.7 Macrophages  

PubMed Central

Artepillin C (3,5-diprenyl-4-hydroxycinnamic acid) is the main bioactive component of Brazilian green propolis. The aim of this study was to investigate the anti-inflammatory effect of artepillin C on LPS + IFN-?- or PMA-stimulated RAW264.7 macrophages. The cell viability was evaluated by MTT and LDH assays. The radical scavenging ability was determined using DPPH• and ABTS•+. ROS and RNS generation was analyzed by chemiluminescence. NO concentration was detected by the Griess reaction. The release of various cytokines by activated RAW264.7 cells was measured in the culture supernatants using a multiplex bead array system based on xMAP technology. NF-?B activity was confirmed by the ELISA-based TransAM NF-?B kit. At the tested concentrations, the compound did not decrease the cell viability and did not cause the cytotoxicity. Artepillin C exerted strong antioxidant activity, significantly inhibited the production of ROS, RNS, NO, and cytokine IL-1?, IL-3, IL-4, IL-5, IL-9, IL-12p40, IL-13, IL-17, TNF-?, G-CSF, GM-CSF, MCP-1, MIP-1?, MIP-1?, RANTES, and KC, and markedly blocked NF-?B expression in stimulated RAW264.7 macrophages. Our findings provide new insights for understanding the mechanism involved in the anti-inflammatory effect of artepillin C and support the application of Brazilian green propolis in complementary and alternative medicine. PMID:23781267

Czuba, Zenon P.; Krol, Wojciech

2013-01-01

340

Enhanced antitumoral efficacy by intratumoral perfusion of activated macrophages associated with photodynamic therapy  

NASA Astrophysics Data System (ADS)

Experiments were performed on five batches of Wistar inbred rats with Walker-256 carcinosarcoma receiving photodynamic therapy (PDT), rMuIFN-gamma activated macrophages (AM(Phi) ) or associated therapy (PDT-AM(Phi) -A; PDT-AM(Phi) -B); the control batch (HBSS) consisted of animals with untreated Walker-256 tumors. The results were as follows: the sole treatment (PDT, AM(Phi) ) gave survival rates between 57.2 and 57.7% and cure rates ranging from 23.1 to 34.3%. The 'combined' therapy in multiple doses increased significantly (87.9%) the survival rate of tumor bearing rats as well as the rate of complete tumor regression (72.7%). Cell-mediated immunity test values in batches III and IV exposed to multiple doses of PDT-AM(Phi) showed higher values as compared to the values noticed in batches I - II and the control batch V, performed at 12 and 21 days post-treatment. Summing up, these results demonstrate that 'combined' photodynamic treatment and biotherapy with interferon activated macrophages stimulate cell-mediated antitumoral activity, increase survival rates and reduce incidence of Walker-256 carcinosarcoma in rat model.

Dima, Vasile F.; Vasiliu, Virgil V.; Laky, Dezideriu; Ionescu, Paul; Dima, Stefan V.

1996-01-01

341

A Novel Accessory Molecule Trim59 Involved in Cytotoxicity of BCG-Activated Macrophages  

PubMed Central

BCG-activated macrophages (BAM) could kill the tumor cells through cell-cell contact. In this process membrane proteins play an important role. However, up to date, few membrane proteins were revealed. In this study, we selected a surface molecule named Trim59, which was specifically expressed on BAM membrane (compared with the negative control). We cloned and prokaryoticly expressed the extracellular domain of Trim59, purified the recombinant protein and generated polyclonal antibodies. Immunohistochemistry showed that Trim59 abundantly expressed in spleen, stomach and ovary; intermediately expressed in brain, lung, kidney, muscle and intestine; but not in thymus, liver, heart, uterus. Using the antibodies to block Trim59 on BAM significantly reduced BAM cytotoxicity against MCA207 cells. This demonstrated that Trim59 serves as an indispensable molecule in maintaining BAM activity. Overexpression of Trim59 in Raw264.7 cell line failed to lyse target MCA207 cells, which potentiated Trim59 per se could not enhance macrophage cytotoxicity; on another hand, overexpression of Trim59 enhance the pinocytosis and Phagocytosis activity of Raw-264.7, which imply Trim59 might mediate the cell-molecule interaction. Our results indicate Trim59 might be an essential accessory molecule in mediating BAM tumoricidal functions; and Trim59 is a phagocytosis-correlated molecule. PMID:22949172

Zhao, Xiangfeng; Liu, Qihui; Du, Baiqiu; Li, Peng; Cui, Qu; Han, Xiao; Du, Bairong; Yan, Dongmei; Zhu, Xun

2012-01-01

342

Macrophage-mediated angiogenic activation of outgrowth endothelial cells in co-culture with primary osteoblasts.  

PubMed

The successful vascularisation of complex tissue engineered constructs for bone regeneration is still a major challenge in the field of tissue engineering. In this context, co-culture systems of endothelial cells and osteoblasts represent a promising approach to advance the formation of a stable vasculature as well as an excellent in vitro model to identify factors that positively influence bone healing processes, including angiogenesis. Under physiological conditions, the activation phase of angiogenesis is mainly induced by hypoxia or inflammation. Inflammatory cells such as macrophages secrete proinflammatory cytokines and proangiogenic growth factors, finally leading to the formation of new blood vessels. The aim of this study was to investigate if macrophages might positively influence the formation of microvessel-like structures via inflammatory mechanisms in a co-culture system consisting of human outgrowth endothelial cells (OECs) and primary osteoblasts. Treatment of co-cultures with macrophages (induced from THP-1) resulted in a higher number of microvessel-like structures formed by OECs compared to the co-culture. This change correlated with a significantly higher concentration of the proangiogenic VEGF in cell culture supernatants of triple-cultures and was accompanied by an increase in the expression of different proinflammatory cytokines, such as IL-6, IL-8 and TNF?. In addition, the expression of E-selectin and ICAM-1, adhesion molecules which are strongly involved in the interaction between leukocytes and endothelial cells during the process of inflammation was also found to be higher in triple-cultures compared to the double co-cultures, documenting an ongoing proinflammatory stimulus. These results raise the possibility of actively using pro-inflammatory stimuli in a tissue engineering context to accelerate healing mechanisms. PMID:24554272

Dohle, E; Bischoff, I; Böse, T; Marsano, A; Banfi, A; Unger, R E; Kirkpatrick, C J

2014-01-01

343

Mycobacterial Trehalose Dimycolate Reprograms Macrophage Global Gene Expression and Activates Matrix Metalloproteinases  

PubMed Central

Trehalose 6,6?-dimycolate (TDM) is a cell wall glycolipid and an important virulence factor of mycobacteria. In order to study the role of TDM in the innate immune response to Mycobacterium tuberculosis, microarray analysis was used to examine gene regulation in murine bone marrow-derived macrophages in response to 90-?m-diameter polystyrene microspheres coated with TDM. A large number of genes, particularly those involved in the immune response and macrophage function, were up- or downregulated in response to these TDM-coated beads compared to control beads. Genes involved in the immune response were specifically upregulated in a myeloid differentiation primary response gene 88 (MyD88)-dependent manner. The complexity of the transcriptional response also increased greatly between 2 and 24 h. Matrix metalloproteinases (MMPs) were significantly upregulated at both time points, and this was confirmed by quantitative real-time reverse transcription-PCR (RT-PCR). Using an in vivo Matrigel granuloma model, the presence and activity of MMP-9 were examined by immunohistochemistry and in situ zymography (ISZ), respectively. We found that TDM-coated beads induced MMP-9 expression and activity in Matrigel granulomas. Macrophages were primarily responsible for MMP-9 expression, as granulomas from neutrophil-depleted mice showed staining patterns similar to that for wild-type mice. The relevance of these observations to human disease is supported by the similar induction of MMP-9 in human caseous tuberculosis (TB) granulomas. Given that MMPs likely play an important role in both the construction and breakdown of tuberculous granulomas, our results suggest that TDM may drive MMP expression during TB pathogenesis. PMID:23264051

Kim, Mi Jeong; Rhoades, Elizabeth R.; Allavena, Rachel E.; Ehrt, Sabine; Wainwright, Helen C.; Russell, David G.; Rohde, Kyle H.

2013-01-01

344

Macrophages enhance the radiosensitizing activity of lipid A: A novel role for immune cells in tumor cell radioresponse  

SciTech Connect

Purpose: This study examines whether activated macrophages may radiosensitize tumor cells through the release of proinflammatory mediators. Methods and materials: RAW 264.7 macrophages were activated by lipid A, and the conditioned medium (CM) was analyzed for the secretion of cytokines and the production of nitric oxide (NO) through inducible nitric oxide synthase (iNOS). EMT-6 tumor cells were exposed to CM and analyzed for hypoxic cell radiosensitivity. The role of nuclear factor (NF)-{kappa}B in the transcriptional activation of iNOS was examined by luciferase reporter gene assay. Results: Clinical immunomodulator lipid A, at a plasma-relevant concentration of 3 {mu}g/mL, stimulated RAW 264.7 macrophages to release NO, tumor necrosis factor (TNF)-{alpha}, and other cytokines. This in turn activated iNOS-mediated NO production in EMT-6 tumor cells and drastically enhanced their radiosensitivity. Radiosensitization was abrogated by the iNOS inhibitor aminoguanidine but not by a neutralizing anti-TNF-{alpha} antibody. The mechanism of iNOS induction was linked to NF-{kappa}B but not to JAK/STAT signaling. Interferon-{gamma} further increased the NO production by macrophages to a level that caused radiosensitization of EMT-6 cells through the bystanding effect of diffused NO. Conclusions: We demonstrate for the first time that activated macrophages may radiosensitize tumor cells through the induction of NO synthesis, which occurs in both tumor and immune cells.

Ridder, Mark de [Academic Hospital, Free University Brussels (A.Z.-V.U.B.), Oncology Center, Cancer Research Unit, Brussels (Belgium)]. E-mail: Mark.De.Ridder@vub.ac.be; Verovski, Valeri N. [Academic Hospital, Free University Brussels (A.Z.-V.U.B.), Oncology Center, Cancer Research Unit, Brussels (Belgium); Darville, Martine I. [Laboratory of Experimental Medicine, Universite Libre de Bruxelles (ULB), Brussels (Belgium); Berge, Dirk L. van den [Academic Hospital, Free University Brussels (A.Z.-V.U.B.), Oncology Center, Cancer Research Unit, Brussels (Belgium); Monsaert, Christinne [Academic Hospital, Free University Brussels (A.Z.-V.U.B.), Oncology Center, Cancer Research Unit, Brussels (Belgium); Eizirik, Decio L. [Academic Hospital, Free University Brussels (A.Z.-V.U.B.), Oncology Center, Cancer Research Unit, Brussels (Belgium); Storme, Guy A. [Academic Hospital, Free University Brussels (A.Z.-V.U.B.), Oncology Center, Cancer Research Unit, Brussels (Belgium)

2004-10-01

345

Assessment and comparison of immunoregulatory activity of four hydrosoluble fractions of Angelica sinensis in vitro on the peritoneal macrophages in ICR mice  

Microsoft Academic Search

Angelica sinensis (Oliv) Diels, a traditional oriental herbal medicine, is known to have immunostimulatory and antitumor effects. In this paper, four hydrosoluble fractions were obtained and purified from A. sinensis including: Angelica polysaccharide, oligosaccharides (Angelica oligosaccharide and Angelica sucrose) and Angelica total amino acid, named APS, AOS, AS, and TAA, respectively. Moreover, the immunomodulatory activity of these four fractions on

Ying Chen; Jin-ao Duan; Dawei Qian; Jianming Guo; Bingsheng Song; Ming Yang

2010-01-01

346

Inflammation, Macrophage in Cancer Progression and Chinese Herbal Treatment  

PubMed Central

Inflammation is associated with cancer development, and has been recognized as the seventh hallmarks of the cancer. Cancer-related inflammation can be activated by genetic or epigenetic changes in cancer cells (intrinsic pathway) or mediated by tumor-infiltrating immune cells (extrinsic pathway). Immune cells involved in cancer-related inflammation mainly including tumor-associated macrophages or M2 macrophages, neutrophils, dendritic cells, mast cells, and lymphocytes. As major players of the cancer-related inflammation, M2 macrophages, secreting various of growth factors, immunomodulatory cytokines and matrix metalloproteinases, participate in remodeling of extracellular matrix, contribute to cancer invasion and metastasis, angiogenesis, and inhibit anti-cancer immunity. Inflammation has been considered as an important target for cancer therapy. Some Chinese herbal ingredients have been confirmed to be effective in inhibit inflammation related gene expression in cancer cells, such as COX-2 and NF-B. However, there is a shortage of study on Chinese herb or herbal ingredient against extrinsic cancer inflammation, especially in tumor-associated macrophages. Related studies may provide new insight into cancer treatment. PMID:24826036

Deng, Shan; Hu, Bing; Shen, Ke-Ping; Xu, Ling

2012-01-01

347

HIV-1 Nef Impairs Key Functional Activities in Human Macrophages through CD36 Downregulation  

PubMed Central

Monocytes and macrophages utilize the class A and B scavenger receptors to recognize and perform phagocytosis of invading microbes before a pathogen-specific immune response is generated. HIV-1 Nef protein affects the innate immune system impairing oxidative burst response and phagocytic capacity of macrophages. Our data show that exogenous recombinant myristoylated Nef protein induces a marked CD36 downregulation in monocytes from Peripheral Blood Mononuclear Cells, in Monocyte-Derived Macrophages (MDMs) differentiated by cytokines and in MDMs contained in a mixed culture obtained expanding PBMCs under Human Erythroid Massive Amplification condition. Under the latter culture condition we identify three main populations after 6 days of expansion: lymphocytes (37.8±14.7%), erythroblasts (46.7±6.1%) and MDMs (15.7±7.5%). The Nef addition to the cell culture significantly downregulates CD36 expression in MDMs, but not in erythroid cells. Furthermore, CD36 inhibition is highly specific since it does not modify the expression levels of other MDM markers such as CD14, CD11c, CD86, CD68, CD206, Toll-like Receptor 2 and Toll-like Receptor 4. Similar results were obtained in MDMs infected with VSV-G pseudotyped HIV-1-expressing Nef. The reduced CD36 membrane expression is associated with decrease of correspondent CD36 mRNA transcript. Furthermore, Nef-induced CD36 downregulation is linked to both impaired scavenger activity with reduced capability to take up oxidized lipoproteins and to significant decreased phagocytosis of fluorescent beads and GFP-expressing Salmonella tiphymurium. In addition we observed that Nef induces TNF-? release in MDMs. Although these data suggest a possible involvement of TNF-? in mediating Nef activity, our results exclude a possible relationship between Nef-induced TNF-? release and Nef-mediated CD36 downregulation. The present work shows that HIV-1 Nef protein may have a role in the strategies elaborated by HIV-1 to alter pathogen disease outcomes, by modulating CD36 expression in macrophages, favoring the onset of opportunistic infections in HIV-1 infected people. PMID:24705461

Olivetta, Eleonora; Tirelli, Valentina; Chiozzini, Chiara; Scazzocchio, Beatrice; Romano, Ignazio; Arenaccio, Claudia; Sanchez, Massimo

2014-01-01

348

Molecular Network Analysis of Endometriosis Reveals a Novel Role for c-Jun Regulated Macrophage Activation  

PubMed Central

Clinical management of endometriosis is limited by the complex relationship between symptom severity, heterogeneous surgical presentations, and variability in clinical outcomes. As a complement to visual classification schemes, molecular profiles of disease activity may improve risk stratification to better inform treatment decisions and identify novel approaches to targeted treatment. Here, we employ a network analysis of information flow within and between inflammatory cells to discern consensus behaviors characterizing patient sub-populations. Unsupervised multivariate analysis of cytokine profiles quantified by multiplex immunoassays identified a subset of patients with a shared “consensus signature” of thirteen elevated cytokines that was associated with common clinical features, but was not observed among patient subpopulations defined by morphologic presentation alone. Enrichment analysis of consensus markers reinforced the primacy of peritoneal macrophage infiltration and activation, which was demonstrably elevated in ex vivo cultures. Although familiar targets of the NF?B family emerged among over-represented transcriptional binding sites for consensus markers, our analysis provides evidence for a previously unrecognized contribution from c-Jun, c-Fos, and AP-1 effectors of mitogen associated kinase signaling. Their crucial involvement in propagation of macrophage-driven inflammatory networks was confirmed via targeted inhibition of upstream kinases. Collectively, these analyses provide in vivo validation of a clinically relevant inflammatory network that may serve as an objective measure for guiding treatment decisions for endometriosis management, and in the future may provide a mechanistic endpoint for assessing efficacy of novel agents aimed at curtailing inflammatory mechanisms that drive disease progression. PMID:24500404

Beste, Michael T.; Pfaffle-Doyle, Nicole; Prentice, Emily A.; Morris, Stephanie N.; Lauffenburger, Douglas A.; Isaacson, Keith B.; Griffith, Linda G.

2014-01-01

349

Macrophage biospecific extraction and HPLC-ESI-MSn analysis for screening immunological active components in Smilacis Glabrae Rhizoma.  

PubMed

A cell-permeable membrane, as typified by Transwell insert Permeable Supports, permit accurate repeatable invasion assays, has been developed as a tool for screening immunological active components in Smilacis Glabrae Rhizoma (SGR). In this research, components in the water extract of SGR (ESGR) might conjugate with the receptors or other targets on macrophages which invaded Transwell inserts, and then the eluate which contained components biospecific binding to macrophages was identified by HPLC-ESI-MS(n) analysis. Six compounds, which could interact with macrophages, were detected and identified. Among these compounds, taxifolin (2) and astilbin (4) were identified by comparing with the chromatography of standards, while the four others including 5-O-caffeoylshikimic acid (1), neoastilbin (3), neoisoastilbin (5) and isoastilbin (6), were elucidated by their structure clearage characterizations of tandem mass spectrometry. Then compound 1 was isolated and purified from SGR, along with 2 and 4, was applied to the macrophage migration and adhesion assay in HUVEC (Human Umbilical Vein Endothelial Cells) -macrophages co-incultured Transwell system for immunological activity assessment. The results showed that compounds 1, 2 and 4 with concentration of 5?M (H), 500nM (M) and 50nM (L) could remarkably inhibit the macrophage migration and adhesion (Vs AGEs (Advanced Glycation End Produces) group, 1-L, 2-H and 4-L groups: p<0.05; other groups: p<0.01). Moreover, 1 and 4 showed satisfactory dose-effect relationship. In conclusion, the application of macrophage biospecific extraction coupled with HPLC-ESI-MS(n) analysis is a rapid, simple and reliable method for screening immunological active components from Traditional Chinese Medicine. PMID:23384550

Zheng, Zhao-Guang; Duan, Ting-Ting; He, Bao; Tang, Dan; Jia, Xiao-Bin; Wang, Ru-Shang; Zhu, Jia-Xiao; Xu, You-Hua; Zhu, Quan; Feng, Liang

2013-04-15

350

IQG-607 abrogates the synthesis of mycolic acids and displays intracellular activity against Mycobacterium tuberculosis in infected macrophages.  

PubMed

In this work, the antitubercular activity of a pentacyano(isoniazid)ferrate(II) compound (IQG-607) was investigated using a macrophage model of Mycobacterium tuberculosis infection. Importantly, treatment of M.-tuberculosis-infected macrophages with IQG-607 significantly diminished the number of CFU compared with the untreated control group. The antitubercular activity of IQG-607 was similar to that observed for the positive control drugs isoniazid and rifampicin. Nevertheless, higher concentrations of IQG-607 produced a significantly greater reduction in bacterial load compared with the same concentrations of isoniazid. Analysis of the mechanism of action of IQG-607 revealed that the biosynthesis of mycolic acids was blocked. The promising activity of IQG-607 in infected macrophages and the experimental determination of its mechanism of action may help in further studies aimed at the development of a new antimycobacterial agent. PMID:24139881

Rodrigues-Junior, Valnês S; dos Santos Junior, André A; Villela, Anne D; Belardinelli, Juan M; Morbidoni, Héctor R; Basso, Luiz A; Campos, Maria M; Santos, Diógenes S

2014-01-01

351

Human peripheral blood monocyte-derived macrophages produce haemolytically active C3 in vitro.  

PubMed Central

The third component of complement (C3) synthesized by human monocyte-derived macrophages has been shown to have the same size and sub-unit structure as serum C3, but haemolytic activity has not been demonstrated. Human monocyte-derived macrophages were cultured from days 4 to 7 in medium without serum, and the conditioned medium was dialysed to remove inhibitors of the C3 assay and concentrated to enhance detection of low amounts of C3. Using these techniques C3 activity was detected routinely. The amount of C3 was 3.4 x 10(7) effective C3 molecules/ml of concentrated tissue culture medium (range 1.0-7.5 x 10(7)), and the number of C3 molecules synthesized by each cell was 4.4 x 10(5), assuming that each cell synthesized C3. The specific activity of the C3 synthesized by the monocytes was the same as the specific activity of C3 that had been purified from serum and then incubated with the cells and processed in the same manner as the monocyte media. Synthesis as the basis for the presence of the C3 activity in the medium was indicated by an inhibition of production of the C3 activity of 66 +/- 16% by cycloheximide, 2 micrograms/ml. Thus, human blood monocytes that migrate into areas of inflammation can mature into cells capable of producing C3 which can participate in the complement sequence and thus potentiate inflammation. PMID:6840804

Strunk, R C; Kunke, K S; Giclas, P C

1983-01-01

352

Palmitoleic acid prevents palmitic acid-induced macrophage activation and consequent p38 MAPK-mediated skeletal muscle insulin resistance  

PubMed Central

Obesity and saturated fatty acid (SFA) treatment are both associated with skeletal muscle insulin resistance (IR) and increased macrophage infiltration. However, the relative effects of SFA and unsaturated fatty acid (UFA)-activated macrophages on muscle are unknown. Here, macrophages were treated with palmitic acid, palmitoleic acid or both and the effects of the conditioned medium (CM) on C2C12 myotubes investigated. CM from palmitic acid-treated J774s (palm-mac-CM) impaired insulin signalling and insulin-stimulated glycogen synthesis, reduced Inhibitor ?B? and increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase in myotubes. p38 MAPK inhibition or siRNA partially ameliorated these defects, as did addition of tumour necrosis factor-? blocking antibody to the CM. Macrophages incubated with both FAs generated CM that did not induce IR, while palmitoleic acid-mac-CM alone was insulin sensitising. Thus UFAs may improve muscle insulin sensitivity and counteract SFA-mediated IR through an effect on macrophage activation. PMID:24973767

Talbot, Nicola A.; Wheeler-Jones, Caroline P.; Cleasby, Mark E.

2014-01-01

353

Mycobacterium indicus pranii mediates macrophage activation through TLR2 and NOD2 in a MyD88 dependent manner.  

PubMed

Mycobacterium indicus pranii (MIP) is a non-pathogenic strain of mycobacterium and has been used as a vaccine against tuberculosis and leprosy. Here, we investigated the role of different pattern recognition receptors in the recognition of heat-killed MIP by macrophages. Treatment of macrophages with MIP caused upregulation of pro-inflammatory cytokines (like TNF? and IL-1?) which was mediated through both TLR2 and NOD2, as revealed by our knockdown and/or knockout studies. Mechanistically, MIP-induced macrophage activation was shown to result in NF-?B activation and drastically abrogated by MyD88 deficiency, suggesting its regulation via an MyD88-dependent, NF-?B pathway. Interestingly, the IFN-inducible cytokine, CXCL10, which is known target of the TRIF-dependent TLR pathway was found to be upregulated in response to MIP but, in an MyD88-dependent manner. Collectively, these results demonstrate macrophages to recognize and respond to MIP through a TLR2, NOD2 and an MyD88-dependent pathway. However, further studies should clarify whether additional TLR-dependent or -independent pathways also exist in regulating the full spectrum of MIP action on macrophage activation. PMID:22796586

Pandey, Rajeev Kumar; Sodhi, Ajit; Biswas, Subhra K; Dahiya, Yogesh; Dhillon, Manprit K

2012-08-24

354

Differential regulation of proinflammatory cytokine expression by mitogen-activated protein kinases in macrophages in response to intestinal parasite infection.  

PubMed

Blastocystis is a common enteric protistan parasite that can cause acute, as well as chronic, infection and is associated with irritable bowel syndrome (IBS). However, the pathogenic status of Blastocystis infection remains unclear. In this study, we found that Blastocystis antigens induced abundant expression of proinflammatory cytokines, including interleukin 1? (IL-1?), IL-6, and tumor necrosis factor alpha (TNF-?), in mouse intestinal explants, in mouse colitis colon, and in macrophages. Further investigation utilizing RAW264.7 murine macrophages showed that Blastocystis treatment in RAW264.7 macrophages induced the activation of ERK, JNK, and p38, the three major groups of mammalian mitogen-activated protein (MAP) kinases that play essential roles in the expression of proinflammatory cytokines. ERK inhibition in macrophages significantly suppressed both mRNA and protein expression of IL-6 and TNF-? and mRNA expression of IL-1?. On the other hand, JNK inhibition resulted in reductions in both c-Jun and ERK activation and significant suppression of all three proinflammatory cytokines at both the mRNA and protein levels. Inhibition of p38 suppressed only IL-6 protein expression with no effect on the expression of IL-1? and TNF-?. Furthermore, we found that serine proteases produced by Blastocystis play an important role in the induction of ERK activation and proinflammatory cytokine expression by macrophages. Our study thus demonstrated for the first time that Blastocystis could induce the expression of various proinflammatory cytokines via the activation of MAP kinases and that infection with Blastocystis may contribute to the pathogenesis of inflammatory intestinal diseases through the activation of inflammatory pathways in host immune cells, such as macrophages. PMID:25156742

Lim, Mei Xing; Png, Chin Wen; Tay, Crispina Yan Bing; Teo, Joshua Ding Wei; Jiao, Huipeng; Lehming, Norbert; Tan, Kevin Shyong Wei; Zhang, Yongliang

2014-11-01

355

Interleukin12 Synthesis Is a Required Step in Trehalose Dimycolate-Induced Activation of Mouse Peritoneal Macrophages  

Microsoft Academic Search

Trehalose dimycolate (TDM), a glycolipid present in the cell wall of Mycobacterium spp., is a powerful immunostimulant. TDM primes murine macrophages (Mf) to produce nitric oxide (NO) and to develop antitumoral activity upon activation with low doses of lipopolysaccharide (LPS). In this study, we investigated the ability of TDM to induce interleukin 12 (IL-12) and the role of this cytokine

ISABELLE P. OSWALD; CHARLES M. DOZOIS; JEAN-FRANCOIS PETIT; ANDGENEVIEVE LEMAIRE

1997-01-01

356

In vitro effects of sporobacterin probiotic on the function of donor granulocyte-macrophage cells.  

PubMed

The effects of sporobacterin probiotic (Bakoren Company) on oxidative activity of donor granulocyte-macrophage cells (GMC) were studied in vitro by luminol-dependent chemiluminescent method, and the effects of the probiotic on the production of pro- and anti-inflammatory cytokines were evaluated by ELISA. The probiotic dose-dependently stimulated spontaneous production of free radicals by GMC; combined treatment with immunomodulators likopid, polyoxydonium, and IFN-?2a produced a more potent effect. Sporobacterin stimulated the production of pro- and anti-inflammatory cytokines in cell cultures. These data confirmed the immunomodulatory effect of sporobacterin, an important component in the phagocytic system cells. PMID:23113261

Gabrielyan, N I; Suskova, V S; Suskov, S I; Vologodskaya, N L

2012-09-01

357

Enterococcus faecalis Infection Activates Phosphatidylinositol 3-Kinase Signaling To Block Apoptotic Cell Death in Macrophages.  

PubMed

Apoptosis is an intrinsic immune defense mechanism in the host response to microbial infection. Not surprisingly, many pathogens have evolved various strategies to manipulate this important pathway to benefit their own survival and dissemination in the host during infection. To our knowledge, no attempts have been made to explore the host cell survival signals modulated by the bacterium Enterococcus faecalis. Here, we show for the first time that during early stages of infection, internalized enterococci can prevent host cell (RAW264.7 cells, primary macrophages, and mouse embryonic fibroblasts [MEFs]) apoptosis induced by a wide spectrum of proapoptotic stimuli. Activation of caspase 3 and cleavage of the caspase 3 substrate poly(ADP-ribose) polymerase were inhibited in E. faecalis-infected cells, indicating that E. faecalis protects macrophages from apoptosis by inhibiting caspase 3 activation. This antiapoptotic activity in E. faecalis-infected cells was dependent on the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, which resulted in the increased expression of the antiapoptotic factor Bcl-2 and decreased expression of the proapoptotic factor Bax. Further analysis revealed that active E. faecalis physiology was important for inhibition of host cell apoptosis, and this feature seemed to be a strain-independent trait among E. faecalis isolates. Employing a mouse peritonitis model, we also determined that cells collected from the peritoneal lavage fluid of E. faecalis-infected mice showed reduced levels of apoptosis compared to cells from uninfected mice. These results show early modulation of apoptosis during infection and have important implications for enterococcal pathogenesis. PMID:25267834

Zou, Jun; Shankar, Nathan

2014-12-01

358

Analysis of antioxidant and anti-inflammatory activity of silicon in murine macrophages.  

PubMed

The purpose of this study is to investigate the antioxidant and anti-inflammatory properties of silicon (Si) in the RAW 264.7 murine macrophage cell line. Lipopolysaccharide (LPS) was used to induce inflammatory conditions, and cells were treated with 0, 1, 5, 10, 25, 50, and 100 ?M Si in the form of sodium metasilicate. Tert-butylhydroquinone (TBHQ), a well-known antioxidative substance, was used as a positive control to assess the degree of antioxidative and anti-inflammatory properties of Si. Sodium metasilicate at 100 ?M suppressed LPS-induced nitric oxide generation from macrophages 36 h after treatment. In addition, 50 ?M sodium metasilicate decreased interleukin-6 production, and the degree of suppression was comparable to that of 10 ?M TBHQ treatment. LPS-induced messenger RNA (mRNA) expression of tumor necrosis factor-? and inducible nitric oxide synthase was significantly decreased by 1, 5, 10, and 50 ?M sodium metasilicate. Cyclooxygenase-2 mRNA expression was also suppressed by 1, 5, 25, and 50 ?M sodium metasilicate. Based on these data, Si has the ability to suppress the production of inflammatory cytokines and mediators, possibly through the suppression of radical scavenger activity and down-regulation of gene expression of inflammatory mediators. PMID:24092518

Kim, Eun-Jin; Bu, So-Young; Sung, Mi-Kyung; Kang, Myung-Hwa; Choi, Mi-Kyeong

2013-12-01

359

Therapeutic activation of macrophages and microglia to suppress brain tumor-initiating cells.  

PubMed

Brain tumor initiating cells (BTICs) contribute to the genesis and recurrence of gliomas. We examined whether the microglia and macrophages that are abundant in gliomas alter BTIC growth. We found that microglia derived from non-glioma human subjects markedly mitigated the sphere-forming capacity of glioma patient-derived BTICs in culture by inducing the expression of genes that control cell cycle arrest and differentiation. This sphere-reducing effect was mimicked by macrophages, but not by neurons or astrocytes. Using a drug screen, we validated amphotericin B (AmpB) as an activator of monocytoid cells and found that AmpB enhanced the microglial reduction of BTIC spheres. In mice harboring intracranial mouse or patient-derived BTICs, daily systemic treatment with non-toxic doses of AmpB substantially prolonged life. Notably, microglia and monocytes cultured from glioma patients were inefficient at reducing the sphere-forming capacity of autologous BTICs, but this was rectified by AmpB. These results provide new insights into the treatment of gliomas. PMID:24316889

Sarkar, Susobhan; Döring, Axinia; Zemp, Franz J; Silva, Claudia; Lun, Xueqing; Wang, Xiuling; Kelly, John; Hader, Walter; Hamilton, Mark; Mercier, Philippe; Dunn, Jeff F; Kinniburgh, Dave; van Rooijen, Nico; Robbins, Stephen; Forsyth, Peter; Cairncross, Gregory; Weiss, Samuel; Yong, V Wee

2014-01-01

360

PPAR?-mediated increase in glucose availability sustains chronic Brucella abortus infection in alternatively activated macrophages  

PubMed Central

SUMMARY Eradication of persistent intracellular bacterial pathogens with antibiotic therapy is often slow or incomplete. However, strategies to augment antibiotics are hampered by our poor understanding of the nutritional environment that sustains chronic infection. Here we show that the intracellular pathogen Brucella abortus survives and replicates preferentially in alternatively activated macrophages (AAM), which are more abundant during chronic infection. A metabolic shift induced by peroxisome proliferator activated receptor ? (PPAR?), which increases intracellular glucose availability, is identified as a causal mechanism promoting enhanced bacterial survival in AAM. Glucose uptake was crucial for increased replication of B. abortus in AAM, and chronic infection, as inactivation of the bacterial glucose transporter gluP reduced both intracellular survival in AAM and persistence in mice. Thus, a shift in intracellular nutrient availability induced by PPAR? promotes chronic persistence of B. abortus within AAM and targeting this pathway may aid in eradicating chronic infection. PMID:23954155

Xavier, Mariana N.; Winter, Maria G.; Spees, Alanna M.; den Hartigh, Andreas B.; Nguyen, Kim; Roux, Christelle M.; Silva, Teane M. A.; Atluri, Vidya L.; Kerrinnes, Tobias; Keestra, A. Marijke; Monack, Denise M.; Luciw, Paul A.; Eigenheer, Richard A.; Baumler, Andreas J.; Santos, Renato L.; Tsolis, Renee M.

2013-01-01

361

Manganese promotes increased formation of hydrogen peroxide by activated human macrophages and neutrophils in vitro.  

PubMed

Although pro-inflammatory mechanisms have been implicated in the pathogenesis of manganese (Mn²?)-related neurological and respiratory disorders, relatively little is known about the potential of this metal to interact pro-oxidatively with human phagocytes. The primary objective of the current study was to investigate the effects of Mn²? as MnCl? (0.5-100 µM) on the generation of the reactive oxygen species (ROS), superoxide, hydrogen peroxide (H?O?), and hypohalous acids by isolated human blood neutrophils and monocyte-derived macrophages following activation of these cells with the chemotactic tripeptide, FMLP (1 µM), or the phorbol ester, PMA (25 ng/mL). Generation of ROS was measured using the combination of oxygen consumption, lucigenin/luminol-enhanced chemiluminescence, spectrofluorimetric detection of oxidation of 2,7-dichlorodihydrofluorescein, radiometric assessment of myeloperoxidase (MPO)-mediated protein iodination, release of MPO by ELISA, and spectrophotometric measurement of nitrite formation. Treatment of activated neutrophils with either FMLP or PMA resulted in significantly decreased reactivity of superoxide in the setting of increased formation of H?O? and MPO-mediated iodination, with no detectable effects on either oxygen consumption or MPO release. Similar effects of the metal with respect to superoxide reactivity and H?O? formation were observed with activated macrophages, while generation of NO was unaffected. Taken together with the findings of experiments using cell-free ROS-generating systems, these observations are compatible with a mechanism whereby Mn²?, by acting as a superoxide dismutase mimetic, increases the formation of H?O? by activated phagocytes. If operative in vivo, this mechanism may contribute to the toxicity of Mn²?. PMID:22906169

Mokgobu, M I; Anderson, R; Steel, H C; Cholo, M C; Tintinger, G R; Theron, A J

2012-08-01