Platelet-activating Factor Mediates Endotoxin Tolerance by Regulating Indoleamine 2,3-Dioxygenase-dependent Expression of the Suppressor of Cytokine Signaling 3

Indoleamine 2,3-dioxygenase (IDO) mediates immune tolerance, and suppressor of cytokine signaling 3 (SOCS3) negatively regulates the JAK/STAT signal transduction pathway. We determined previously that platelet-activating factor (PAF) protects mice against LPS-induced endotoxic shock, but its detailed mechanism of action was unknown. We performed survival experiments in IDO+/+ and IDO−/− mice using an LPS-induced endotoxemia model and rated organ injury (neutrophil infiltration and liver function). Using ELISA and Western blotting, we also investigated the mechanism of PAF-mediated endotoxin tolerance during endotoxemia. PAF-mediated endotoxin tolerance was dependent on IDO in vivo and in vitro and was not observed in IDO−/− mice. JAK/STAT signaling, crucial for SOCS3 expression, was also impaired in the absence of IDO. In an IDO- and STAT-dependent manner, PAF mediated a decrease in IL-12 and a dramatic increase in IL-10 and reduced mouse mortality. In addition, PAF attenuated LPS-mediated neutrophil infiltration into the lungs and interactions between neutrophil-like (THP-1) and endothelial cells (human umbilical vein endothelial cells). These results indicate that PAF-mediated endotoxin tolerance is initiated via IDO- and JAK/STAT-dependent expression of SOCS3. Our study has revealed a novel tolerogenic mechanism of IDO action and an important association between IDO and SOCS3 with respect to endotoxin tolerance.

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Seasonal effects of central leptin infusion on secretion of melatonin and prolactin and on SOCS-3 gene expression in ewes

Journal of Endocrinology ◽

10.1677/joe-07-0602 ◽

2008 ◽

Vol 198 (1) ◽

pp. 147-155 ◽

Cited By ~ 30

Author(s):

D A Zieba ◽

M Szczesna ◽

B Klocek-Gorka ◽

E Molik ◽

T Misztal ◽

...

Keyword(s):

Third Ventricle ◽

Plasma Concentrations ◽

Seasonal Effects ◽

Cytokine Signaling ◽

Dependent Manner ◽

Suppressor Of Cytokine Signaling ◽

Medial Basal Hypothalamus ◽

Leptin Sensitivity ◽

Dose Dependent ◽

Short Days

Recent studies have demonstrated photoperiodic changes in leptin sensitivity of seasonal mammals. Herein, we examined the interaction of season (long days (LD) versus short days (SD)) and recombinant ovine leptin (roleptin) on secretion of melatonin and prolactin (PRL) and on mRNA expression of suppressor of cytokine signaling-3 (SOCS-3) in the medial basal hypothalamus (MBH) in sheep. Twenty-four Polish Longwool ewes, surgically fitted with third ventricle (IIIV) cannulas, were utilized in a replicated switchback design involving 12 ewes per season. Within-season and replicate ewes were assigned randomly to one of three treatments (four ewes/treatment) and infused centrally three times at 0, 1 and 2 h beginning at sunset. Treatments were 1) control, Ringer–Locke buffer; 2) L1, roleptin, 0.5 μg/kg BW; and 3) L2, roleptin, 1.0 μg/kg BW. Jugular blood samples were collected at 15-min intervals beginning immediately before the start of infusions and continued for 6 h. At the end of blood sampling, a washout period of at least 3 days elapsed before ewes were re-randomized and treated with one of the treatments described above (four ewes/treatment). Ewes were then killed and brains were collected for MBH processing. Leptin treatments increased (P<0.001) circulating leptin concentrations compared with controls during both seasons in a dose-dependent manner. Overall, mean plasma concentrations of melatonin were greater (P<0.001) during LD than SD. However, leptin treatments increased melatonin concentrations during SD in a dose-dependent manner and decreased it during LD. Similarly, plasma concentrations of PRL were greater (P<0.001) during LD than SD. However, unlike changes in melatonin, circulating PRL decreased (P<0.001) in response to leptin during LD. Semi-quantitative PCR revealed that leptin increased (P<0.001) SOCS-3 expression in the MBH region during LD in a dose-dependent manner. Data provide evidence that secretion of photoperiodic hormones such as melatonin and PRL are inversely regulated by leptin during SD and LD. However, the increase in expression of SOCS-3 in the MBH during LD compared with SD fails to fully explain these effects.

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Suppressor of Cytokine Signaling 3 Suppresses Hepatitis C Virus Replication in an mTOR-Dependent Manner

Journal of Virology ◽

10.1128/jvi.02484-09 ◽

2010 ◽

Vol 84 (12) ◽

pp. 6060-6069 ◽

Cited By ~ 33

Author(s):

Run-Xuan Shao ◽

Leiliang Zhang ◽

Lee F. Peng ◽

Eileen Sun ◽

Woo Jin Chung ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Full Length ◽

Cytokine Signaling ◽

Type I ◽

Dependent Manner ◽

Suppressor Of Cytokine Signaling ◽

Protein Levels ◽

Infected Cells ◽

Ifn Treatment

ABSTRACT We and others have observed that hepatic levels of suppressor of cytokine signaling 3 (SOCS3) are significantly higher in persons with chronic hepatitis C, particularly those who are nonresponders to interferon (IFN) treatment, than in healthy individuals. However, the relationship between SOCS3 and hepatitis C virus (HCV) replication remains unclear. Given its putative role, we hypothesized that SOCS3 is permissive for viral replication. We therefore used the OR6 cell line, which harbors a genotype 1b full-length HCV replicon, and the genotype 2a full-length HCV strain JFH1 infection system to analyze the effects of SOCS3 overexpression and short hairpin RNA (shRNA)-mediated knockdown on HCV replication. We further analyzed the role of mTOR in the effects of SOCS3 by treating selected cells with rapamycin. OR6 cells and JFH1-infected Huh7.5.1 cells expressed significantly less SOCS3 than control cells. Furthermore, inhibition of HCV replication with the HCV protease inhibitor BILN 2061 restored SOCS3 protein levels. SOCS3 overexpression in OR6 cells and JFH1-infected Huh7.5.1 cells resulted in significantly lower HCV replication than that in the control cells, despite SOCS3-related inhibition of STAT1 phosphorylation and type I IFN signaling. In contrast, JFH1-infected cells with stable SOCS3 knockdown expressed higher levels of HCV proteins and RNA than did control cells. SOCS3-targeting shRNA also knocked down mTOR and phospho-mTOR. The mTOR inhibitor rapamycin reversed the inhibitory effects of SOCS3. In independent investigations, SOCS3 unexpectedly suppressed HCV replication in an mTOR-dependent manner. These findings suggest that increased SOCS3 levels consistently observed in chronic IFN nonresponders may reflect a compensatory host antiviral response to persistent infection and that manipulation of SOCS3/mTOR may offer benefit against HCV infection.

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MicroRNA-155 Participates in Smoke-Inhalation-Induced Acute Lung Injury through Inhibition of SOCS-1

Molecules ◽

10.3390/molecules25051022 ◽

2020 ◽

Vol 25 (5) ◽

pp. 1022 ◽

Cited By ~ 2

Author(s):

Yue Zhang ◽

Yifang Xie ◽

Leifang Zhang ◽

Hang Zhao

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Inflammatory Response ◽

Neutrophil Infiltration ◽

Smoke Inhalation ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

Keratinocyte Chemoattractant ◽

Inflammatory Protein ◽

Macrophage Inflammatory Protein

Smoke inhalation causes acute lung injury (ALI), a severe clinical disease with high mortality. Accumulating evidence indicates that microRNA-155 (miR-155) and suppressor of cytokine signaling 1 (SOCS-1), as mediators of inflammatory response, are involved in the pathogenesis of ALI. In this paper, we explored the proinflammatory mechanism of miR-155 in smoke-inhalation-induced ALI. Our data revealed that smoke inhalation induces miR-155 expression, and miR-155 knockout (KO) significantly ameliorates smoke-inhalation-induced lung injury in mice. Neutrophil infiltration and myeloperoxidase (MPO), macrophage inflammatory protein 2 (MIP-2) and keratinocyte chemoattractant (KC) expressions were decreased in miR-155–/– mice after smoke inhalation as well. Real-time RT-PCR and immunoblotting results showed that SOCS-1 level was remarkably increased in miR-155–/– mice after smoke exposure. Furthermore, the experiments performed in isolated miR-155 KO pulmonary neutrophils demonstrated that the lack of SOCS-1 enhanced inflammatory cytokines (MIP-2 and KC) secretion in response to smoke stimulation. In conclusion, smoke induces increased expression of miR-155, and miR-155 is involved in inflammatory response to smoke-inhalation-induced lung injury by inhibiting the expression of SOCS-1.

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Glomerular endothelial cells respond to calcium-mobilizing agonists with release of EDRF

AJP Renal Physiology ◽

10.1152/ajprenal.1990.258.5.f1295 ◽

1990 ◽

Vol 258 (5) ◽

pp. F1295-F1303 ◽

Cited By ~ 3

Author(s):

P. A. Marsden ◽

T. A. Brock ◽

B. J. Ballermann

Keyword(s):

Endothelial Cells ◽

Calcium Concentration ◽

Mesangial Cells ◽

Platelet Activating Factor ◽

Cytosolic Calcium ◽

Dependent Manner ◽

Glomerular Mesangial Cells ◽

Concentration Dependent Manner ◽

Glomerular Function ◽

Glomerular Endothelial Cells

To determine whether glomerular endothelial cells (GEN) may play a role in the local control of glomerular function by releasing endothelium-derived relaxing factor (EDRF), the effect of several agonists on GEN cytosolic calcium concentration ([Ca2+]i) and GEN EDRF release was determined. Bradykinin, ATP, thrombin, and platelet-activating factor (PAF) all increased [Ca2+]i in GEN in a concentration-dependent manner, whereas serotonin, acetylcholine, phenylephrine, and endothelin-1 were without effect. Coincubation of glomerular mesangial cells (GMC) with GEN augmented mesangial cell guanosine 3',5'-cyclic monophosphate (cGMP) content five- to sixfold, Bradykinin elicited a further concentration-dependent increase in GMC cGMP content in the presence but not absence of GEN. The GEN-dependent bradykinin-stimulated GMC cGMP accumulation was abolished by hemoglobin and methylene blue, blunted by gossypol, and augmented by superoxide dismutase. Other agonists capable of augmenting GEN [Ca2+]i also stimulated GMC cGMP accumulation in the presence but not in the absence of GEN. Thus cultured GEN release a factor that stimulates cGMP accumulation in adjacent mesangial cells which has the pharmacological characteristics of EDRF.

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Cannabinoid-induced autophagy regulates suppressor of cytokine signaling-3 in intestinal epithelium

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00317.2013 ◽

2014 ◽

Vol 307 (2) ◽

pp. G140-G148 ◽

Cited By ~ 15

Author(s):

Luan C. Koay ◽

Rachael J. Rigby ◽

Karen L. Wright

Keyword(s):

Protein Expression ◽

Intestinal Epithelium ◽

Intestinal Inflammation ◽

Cytokine Signaling ◽

Dependent Manner ◽

Suppressor Of Cytokine Signaling ◽

Cannabinoid Type 1 Receptor ◽

The Impact ◽

Socs3 Protein

Autophagy is a catabolic process involved in homeostatic and regulated cellular protein recycling and degradation via the lysosomal degradation pathway. Emerging data associate impaired autophagy, increased activity in the endocannabinoid system, and upregulation of suppressor of cytokine signaling-3 (SOCS3) protein expression during intestinal inflammation. We have investigated whether these three processes are linked. By assessing the impact of the phytocannabinoid cannabidiol (CBD), the synthetic cannabinoid arachidonyl-2′-chloroethylamide (ACEA), and the endocannabinoid N-arachidonoylethanolamine (AEA) on autophagosome formation, we explored whether these actions were responsible for cyclic SOCS3 protein levels. Our findings show that all three cannabinoids induce autophagy in a dose-dependent manner in fully differentiated Caco-2 cells, a model of mature intestinal epithelium. ACEA and AEA induced canonical autophagy, which was cannabinoid type 1 receptor-mediated. In contrast, CBD was able to bypass the cannabinoid type 1 receptor and the canonical pathway to induce autophagy, albeit to a lesser extent. Functionally, all three cannabinoids reduced SOCS3 protein expression, which was reversed by blocking early and late autophagy. In conclusion, the regulatory protein SOCS3 is regulated by autophagy, and cannabinoids play a role in this process, which could be important when therapeutic applications for the cannabinoids in inflammatory conditions are considered.

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Isoproterenol is a positive regulator of the suppressor of cytokine signaling-3 gene expression in 3T3-L1 adipocytes

Journal of Endocrinology ◽

10.1677/joe.0.1750727 ◽

2002 ◽

Vol 175 (3) ◽

pp. 727-733 ◽

Cited By ~ 17

Author(s):

M Fasshauer ◽

J Klein ◽

U Lossner ◽

R Paschke

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Mrna Expression ◽

Adenylyl Cyclase ◽

Insulin Signaling ◽

Tnf Alpha ◽

Cytokine Signaling ◽

Dependent Manner ◽

Suppressor Of Cytokine Signaling ◽

Beta Adrenergic

SOCS (suppressor of cytokine signaling)-3 has recently been shown to be an insulin- and tumor necrosis factor (TNF)-alpha-induced negative regulator of insulin signaling. To further clarify a potential involvement of SOCS-3 in the development of insulin resistance, we measured differentiation-dependent SOCS-3 mRNA expression in 3T3-L1 adipocytes and studied its regulation by various hormones known to impair insulin signaling using quantitative real-time RT-PCR. There was a differentiation-dependent downregulation of SOCS-3 mRNA by 50% over the 9 day adipocyte differentiation course. Interestingly, besides insulin and TNF-alpha, chronic treatment of differentiated 3T3-L1 cells with 10 microM isoproterenol for 16 h stimulated SOCS-3 gene expression by about 3.5-fold. Furthermore, isoproterenol stimulated SOCS-3 mRNA expression in a dose-dependent manner with significant activation detectable at concentrations as low as 10 nM isoproterenol. Moreover, a strong 27- and 47-fold activation of SOCS-3 mRNA expression could be seen after 1 h of isoproterenol and GH treatment respectively. The stimulatory effect of isoproterenol could be almost completely reversed by pretreatment of 3T3-L1 cells with the beta-adrenergic antagonist propranolol. Finally, isoproterenol's action could be mimicked by stimulation of G(S)-proteins with cholera toxin and of adenylyl cyclase with forskolin and dibutyryl cAMP. Taken together, our results demonstrate a differentiation-dependent downregulation of SOCS-3 in adipocytes and suggest that SOCS-3 gene expression is stimulated by beta-adrenergic agents via activation of a G(S)-protein-adenylyl cyclase-dependent pathway. As SOCS-3 is a novel inhibitor of insulin signaling, the data support a possible role of this protein as a selectively regulated mediator of catecholamine-induced insulin resistance.

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Endothelial cells potentiate phagocytic killing by macrophages via platelet-activating factor release

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.278.1.h269 ◽

2000 ◽

Vol 278 (1) ◽

pp. H269-H276 ◽

Cited By ~ 7

Author(s):

Tetsuhiro Owaki ◽

Avedis Meneshian ◽

Kosei Maemura ◽

Sonshin Takao ◽

Dajie Wang ◽

...

Keyword(s):

Endothelial Cells ◽

Platelet Activating Factor ◽

Peritoneal Macrophages ◽

Dependent Manner ◽

Macrophage Phagocytosis ◽

Monocytes And Macrophages ◽

Paf Receptor ◽

Factor Α ◽

Dose Dependent ◽

Phagocytic Killing

The immunomodulatory function of endothelial cells (EC) includes the initiation of leukocyte margination, diapedesis, and activation through the upregulation of various cell surface-associated molecules. However, the effect that EC have on the phagocytic function of neighboring monocytes and macrophages is less well described. To address this issue, microvascular EC were cocultured with murine peritoneal macrophages, first in direct contact, then in a noncontact coculture system, and macrophage phagocytosis and phagocytic killing were assessed. The presence of increasing concentrations of EC resulted in a dose-dependent increase in macrophage phagocytic killing. This stimulatory effect was inhibited in a dose-dependent manner by the pretreatment of macrophage/EC cocultures with WEB-2086 or CV-6209, specific platelet-activating factor (PAF)-receptor antagonists, but not by anti-tumor necrosis factor-α, anti-interleukin (IL)-1α, or anti-IL-1β. Furthermore, the effect was reproduced in the absence of EC by the exogenous administration of nanomolar concentrations of PAF. Microvascular EC potentiate macrophage phagocytic killing via the release of a soluble signal; PAF appears to be an important component of that signal.

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Proteasomal Degradation of Indoleamine 2,3-Dioxygenase in CD8+ Dendritic Cells is Mediated by Suppressor of Cytokine Signaling 3 (SOCS3)

International Journal of Tryptophan Research ◽

10.4137/ijtr.s3971 ◽

2010 ◽

Vol 3 ◽

pp. IJTR.S3971 ◽

Cited By ~ 16

Author(s):

Maria T. Pallotta ◽

Ciriana Orabona ◽

Claudia Volpi ◽

Ursula Grohmann ◽

Paolo Puccetti ◽

...

Keyword(s):

Dendritic Cells ◽

Proteasomal Degradation ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

Indoleamine 2,3 Dioxygenase ◽

Rate Limiting Step ◽

Inflammatory Stimuli ◽

Tryptophan Catabolism ◽

Rate Limiting ◽

Specific Pathway

Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial and rate-limiting step of tryptophan catabolism in a specific pathway, resulting in a series of extracellular messengers collectively known as kynurenines. IDO has been recognized as an authentic regulator of immunity not only in mammalian pregnancy, but also in infection, autoimmunity, inflammation, allergy, transplantation, and neoplasia. Its suppressive effects are mostly mediated by dendritic cells (DCs) and involve tryptophan deprivation and/or production of kynurenines, which act on IDO-negative DCs as well as CD4+ and CD8+ T cells. We have found that mouse IDO contains two tyrosine residues within two distinct putative immunoreceptor tyrosine-based inhibitory motifs, VPY115CEL and LLY253EGV. We have also found that Suppressor of Cytokine Signaling 3 (SOCS3)—known to interact with phosphotyrosine-containing peptides and be selectively induced by interleukin 6 (IL-6)—binds mouse IDO, recruits the ECS (Elongin-Cullin-SOCS) E3 ligase, and targets the IDO/SOCS3 complex for proteasomal degradation. This event underlies the ability of IL-6 to convert otherwise tolerogenic, IDO-competent DCs into immunogenic cells. Thus onset of immunity in response to antigen within an early inflammatory context demands that IDO be degraded in tolerogenic DCs. These studies support the finding that IDO is regulated by proteasomal degradation in response to immunogenic and inflammatory stimuli.

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