Cutting Edge: IL-10-Independent STAT3 Activation by<i>Toxoplasma gondii</i>Mediates Suppression of IL-12 and TNF-α in Host Macrophages

Butcher, Barbara A.; Kim, Leesun; Panopoulos, Athanasia D.; Watowich, Stephanie S.; Murray, Peter J.; Denkers, Eric

doi:10.4049/jimmunol.174.6.3148

Cited by 136 publications

(122 citation statements)

References 31 publications

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“…STAT3 is also known to play major roles in infection with Salmonella and Toxoplasma. Rapid and sustained activation of STAT3 was observed in hosts after cell invasion by T. gondii and Salmonella typhi [33,34]. Our data further indicated that among the different transcription factors that function in an IL-10-dependent manner, STAT3 was the most potent one, which was activated during L. donovani infection and, in turn, regulated IL-4Ra expression and arginase activation.…”

supporting

confidence: 65%

Expression of IL‐10‐triggered STAT3‐dependent IL‐4Rα is required for induction of arginase 1 in visceral leishmaniasis

et al. 2011

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Although enhanced macrophage-specific arginase activity is directly related to increased parasite burden in cutaneous leishmaniasis (CL), the regulation and precise role of arginase in the disease outcome of visceral leishmaniasis (VL) has yet to be explored. As in CL, BALB/c mice infected with Leishmania donovani showed increased levels of arginase in acute infection. Arginase 1 is the major isoform associated with infection and while the IL-4-induced arginase pathway is operative in CL, IL-10 plays a crucial role in modulating arginase activity in VL, although a synergism with IL-4 is required. IL-10, in combination with IL-4, regulated both in vivo and ex vivo arginase 1 induction in a STAT6 and C/EBPbdependent fashion. Further investigation toward the cause of such synergism suggests that induction of a STAT3-dependent IL-10-mediated cascade in VL triggers the expression and surface localization of the IL-4 receptor alpha (IL-4Ra) which, in turn, enhances IL-4 responsiveness toward STAT6 and C/EBPb-dependent signaling for arginase 1. This could also offer a mechanistic explanation for the fact that, in spite of the low level of IL-4 in VL, enhanced IL-4-Ra expression by IL-10 might markedly amplify IL-4-mediated arginase 1 signaling and provide a possible mechanism for synergistic induction of arginase 1.Keywords: Arginase 1 . IL-4 . IL-10 . IL-4 receptor a . Visceral leishmaniasis IntroductionArginase is classically considered as a rate-limiting enzyme of the urea cycle in liver, but has been found to be present in a number of organs and tissues where the urea cycle is not operative. To date, two distinct isoforms of arginase have been identified in mammals. They are encoded by different genes differing in their cellular localization as well as their mode of regulation: type 1 arginase, a cytosolic enzyme expressed at high levels in liver, and type 2 arginase, a mitochondrial enzyme found in several tissues in addition to liver [1]. A growing body of evidence suggests that arginase induction is correlated with parasite-specific immunosuppression of host, thereby facilitating pathogen survival and growth inside the hostile environment of phagocytic cells. Macrophages were found to upregulate arginase 1 expression upon activation by Th2 cytokines and shown to have a detrimental role in parasite infection by limiting the Th1-dependent parasite clearance [2]. Interestingly, cAMP and TGFb are known to induce arginase 1 induction in macrophages [3]. In Chagas disease, induction of the arginase pathway could be used by Trypanosoma cruzi to spread inside host [4]. Arginase activity was triggered in macrophages from mice infected with the helminth Schistosoma mansoni and was associated with an increase in concentration of circulating L-ornithine-derived polyamines [5]. Intracellular pathogens like Salmonella enterica and Mycobacterium tuberculosis also utilize host arginase for their own 992survival within the macrophages [6,7]. Moreover, in bacteria like Helicobacter pyroli, arginase plays a major role in its surv...

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confidence: 65%

Expression of IL‐10‐triggered STAT3‐dependent IL‐4Rα is required for induction of arginase 1 in visceral leishmaniasis

et al. 2011

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“…Several reports have revealed mechanisms responsible for STAT3-mediated attenuation of immune responses. For example, activated STAT3 was shown to suppress LPS-induced IL-6, tumor necrosis factor ␣, and IL-12 gene expression in macrophages and in dendritic cells (57,58). STAT3 deficiency (or inactivation) makes the mutant mice highly susceptible to LPS shock and results in increased production of inflammatory cytokines such as tumor necrosis factor ␣, IL-1, and IFN␥ from macrophages or neutrophils (59,60).…”

Section: Discussionmentioning

confidence: 99%

Cannabinoids Δ9-Tetrahydrocannabinol and Cannabidiol Differentially Inhibit the Lipopolysaccharide-activated NF-κB and Interferon-β/STAT Proinflammatory Pathways in BV-2 Microglial Cells

Kozela

Pietr

Juknat

et al. 2010

Journal of Biological Chemistry

229

193

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Cannabinoids have been shown to exert anti-inflammatory activities in various in vivo and in vitro experimental models as well as ameliorate various inflammatory degenerative diseases. However, the mechanisms of these effects are not completely understood. Using the BV-2 mouse microglial cell line and lipopolysaccharide (LPS) to induce an inflammatory response, we studied the signaling pathways engaged in the anti-inflammatory effects of cannabinoids as well as their influence on the expression of several genes known to be involved in inflammation. We found that the two major cannabinoids present in marijuana, ⌬ 9 -Tetrahydrocannabinol (THC) 3 is a major constituent of Cannabis and serves as an agonist of the cannabinoid receptors CB1 (located mainly in neural cells) and CB2 (located mainly on immune cells). The second major constituent of Cannabis extract is cannabidiol (CBD), which is virtually inactive at the CB1 and CB2 receptors (1). Thus, because of its negligible activity at the CB1 receptor, CBD lacks the psychoactive effects that accompany the use of THC. Moreover, CBD was demonstrated to antagonize some undesirable effects of THC, including intoxication, sedation, and tachycardia, while sharing neuroprotective, anti-oxidative, anti-emetic, and anti-carcinogenic properties (2-4). Both THC and CBD have been shown to exert anti-inflammatory properties and to modulate the function of immune cells, including suppression of humoral response, immune cell proliferation, maturation, and migration, and antigen presentation (5-9). Despite increasing amounts of such observations, the molecular mechanisms involved in these cannabinoid-mediated effects are not yet fully understood.Microglial cells are resident macrophages of the central nervous system and serve as early host defense against pathogens. Activation of microglial cells leads to the release of proinflammatory and neurotoxic factors and serves as part of the neuroinflammatory process (10). The BV-2 murine microglial cell line is known to retain morphological, phenotypic, and functional properties associated with freshly isolated microglia such as expression of nonspecific esterase activity, phagocytic ability, and the absence of peroxidase activity (11,12). Furthermore, these cells release lysozyme and, when stimulated, interleukin (IL)-1 and tumor necrosis factor ␣ (11, 12). Close similarities between BV-2 and primary microglia in mechanisms mediating microglial stimulations, e.g. by lipopolysaccharide (LPS), S100B, or ␤-amyloid, were reported (13). These properties make BV-2 cells an appropriate model for studying the activation of microglia in vitro. It has recently been shown that BV-2 cells express elements of the cannabinoid signaling systems, including the presence of endocannabinoids, i.e. anandamide and 2-arachidonoylglycerol, and cannabinoid or cannabinoid- 3 The abbreviations used are: THC, ⌬ 9 -tetrahydrocannabinol; CBD, cannabidiol; abn-CBD, abnormal cannabidiol; STAT, signal transducers and activators of transcription; IL, interleukin; IFN, ...

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“…We also show that the inhibitory potential is directly related to the process of infection (Transwell experiments, live vs killed parasites) and is not mediated by secreted factors, including IL-10. Recently, it has been shown that T. gondii inhibits the NF-B pathway in a STAT3-dependent manner (9). STAT3 is the crucial transmitter of the inhibitory cytokine IL-10, yet the inhibitory effects were IL-10 independent.…”

Section: Discussionmentioning

confidence: 99%

Induction of Suppressor of Cytokine Signaling-1 byToxoplasma gondiiContributes to Immune Evasion in Macrophages by Blocking IFN-γ Signaling

Zimmermann

Murray

Heeg

et al. 2006

The Journal of Immunology

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Toxoplasma gondii is an intracellular parasite that survives and multiplies in professional phagocytes such as macrophages. Therefore, T. gondii has to cope with the panel of antimicrobial host immune mechanisms, among which IFN-γ plays a crucial role. We report in this study that in vitro infection of murine macrophages with viable, but not with inactivated, parasites results in inhibition of IFN-γ signaling within the infected cells. Thus, infection of RAW264.7 macrophages with tachyzoites inhibited IFN-γ-induced STAT-1 tyrosine phosphorylation, mRNA expression of target genes, and secretion of NO. These effects were dependent on direct contact of the host cells with living parasites and were not due to secreted intermediates. In parallel, we report the induction of suppressor of cytokine signaling-1 (SOCS-1), which is a known feedback inhibitor of IFN-γ receptor signaling. SOCS-1 was induced directly by viable parasites. SOCS overexpression in macrophages did not affect tachyzoite proliferation per se, yet abolished the inhibitory effects of IFN-γ on parasite replication. The inhibitory effects of T. gondii on IFN-γ were diminished in macrophages from SOCS-1−/− mice. The results suggest that induction of SOCS proteins within phagocytes due to infection with T. gondii contributes to the parasite’s immune evasion strategies.

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Cutting Edge: IL-10-Independent STAT3 Activation byToxoplasma gondiiMediates Suppression of IL-12 and TNF-α in Host Macrophages

Cited by 136 publications

References 31 publications

Expression of IL‐10‐triggered STAT3‐dependent IL‐4Rα is required for induction of arginase 1 in visceral leishmaniasis

Expression of IL‐10‐triggered STAT3‐dependent IL‐4Rα is required for induction of arginase 1 in visceral leishmaniasis

Cannabinoids Δ9-Tetrahydrocannabinol and Cannabidiol Differentially Inhibit the Lipopolysaccharide-activated NF-κB and Interferon-β/STAT Proinflammatory Pathways in BV-2 Microglial Cells

Induction of Suppressor of Cytokine Signaling-1 byToxoplasma gondiiContributes to Immune Evasion in Macrophages by Blocking IFN-γ Signaling

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