Suppressor of cytokine signaling 1 suppresses muscle differentiation through modulation of IGF-I receptor signal transduction

Angiotensin II exerts a potent dypsogenic stimulus on the hypothalamus, which contributes to its centrally mediated participation in the control of water balance and blood pressure. Repetitive intracerebroventricular (i.c.v.) injections of angiotensin II lead to a loss of effect characterized as physiological desensitization to the peptide's action. In the present study, we demonstrate that angiotensin II induces the expression of suppressor of cytokine signaling (SOCS)-3 via angiotensin receptor 1 (AT1) and JAK-2, mostly located at the median preoptic lateral and anterodorsal preoptic nuclei. SOCS-3 produces an inhibitory effect upon the signal transduction pathways of several cytokines and hormones that employ members of the JAK/STAT families as intermediaries. The partial inhibition of SOCS-3 translation by antisense oligonucleotide was sufficient to significantly reduce the refractoriness of repetitive i.c.v. angiotensin II injections, as evaluated by water ingestion. Thus, by acting through AT1 on the hypothalamus, angiotensin II induces the expression of SOCS-3 which, in turn, blocks further activation of the pathway and consequently leads to desensitization to angiotensin II stimuli concerning its dypsogenic effect.

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Growth Enhancement in Suppressor of Cytokine Signaling 2 (SOCS-2)-Deficient Mice Is Dependent on Signal Transducer and Activator of Transcription 5b (STAT5b)

Molecular Endocrinology ◽

10.1210/mend.16.6.0845 ◽

2002 ◽

Vol 16 (6) ◽

pp. 1394-1406 ◽

Cited By ~ 76

Author(s):

Christopher J. Greenhalgh ◽

Patrick Bertolino ◽

Sylvia L. Asa ◽

Donald Metcalf ◽

Jason E. Corbin ◽

...

Keyword(s):

Postnatal Growth ◽

Cytokine Signaling ◽

Growth Enhancement ◽

Signal Transducer ◽

Primary Hepatocytes ◽

Suppressor Of Cytokine Signaling ◽

Embryonic Fibroblasts ◽

Adult Mice ◽

Igf I ◽

Deficient Mice

Abstract Mice lacking suppressor of cytokine signaling-2 (SOCS-2) exhibit accelerated postnatal growth resulting in adult mice that are 1.3 to 1.5 times the size of normal mice. In this study we examined the somatotrophic pathway to determine whether the production or actions of GH or IGF-I are altered in these mice. We demonstrated that SOCS-2−/− mice do not have elevated GH levels and suffer no major pituitary dysmorphogenesis, and that SOCS-2-deficient embryonic fibroblasts do not have altered IGF-I signaling. Primary hepatocytes from SOCS-2−/− mice, however, did have moderately prolonged signal transducer and activator of transcription 5 signaling in response to GH stimulation. Furthermore, the deletion of SOCS-2 from mice also lacking signal transducer and activator of transcription 5b had little effect on growth, suggesting that the action of SOCS-2 may be the regulation of the GH signaling pathway.

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Suppressor of Cytokine Signaling-3 Inhibits Interleukin-1 Signaling by Targeting the TRAF-6/TAK1 Complex

Molecular Endocrinology ◽

10.1210/me.2005-0301 ◽

2006 ◽

Vol 20 (7) ◽

pp. 1587-1596 ◽

Cited By ~ 104

Author(s):

Helle Frobøse ◽

Sif Groth Rønn ◽

Peter E. Heding ◽

Heidi Mendoza ◽

Philip Cohen ◽

...

Keyword(s):

Signal Transduction ◽

Interleukin 1 ◽

Cytokine Signaling ◽

Nuclear Factor ◽

Tnf Receptor ◽

Suppressor Of Cytokine Signaling ◽

Signaling Complex ◽

Nuclear Factor Κ B ◽

Erk Kinase

Abstract IL-1 plays a major role in inflammation and autoimmunity through activation of nuclear factor κ B (NFκB) and MAPKs. Although a great deal is known about the mechanism of activation of NFκB and MAPKs by IL-1, much less is known about the down-regulation of this pathway. Suppressor of cytokine signaling (SOCS)-3 was shown to inhibit IL-1-induced transcription and activation of NFκB and the MAPKs JNK and p38, but the mechanism is unknown. We show here that SOCS-3 inhibits NFκB-dependent transcription induced by overexpression of the upstream IL-1 signaling molecules MyD88, IL-1R-activated kinase 1, TNF receptor-associated factor (TRAF)6, and TGFβ-activated kinase (TAK)1, but not when the MAP3K MAPK/ERK kinase kinase-1 is used instead of TAK1, indicating that the target for SOCS-3 is the TRAF6/TAK1 signaling complex. By coimmunoprecipitation, it was shown that SOCS-3 inhibited the association between TRAF6 and TAK1 and that SOCS-3 coimmunoprecipitated with TAK1 and TRAF6. Furthermore, SOCS-3 inhibited the IL-1-induced catalytic activity of TAK1. Because ubiquitination of TRAF6 is required for activation of TAK1, we analyzed the role of SOCS-3 on TRAF6 ubiquitination and found that SOCS-3 inhibited ubiquitin modification of TRAF6. These results indicate that SOCS-3 inhibits IL-1 signal transduction by inhibiting ubiquitination of TRAF6, thus preventing association and activation of TAK1.

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Suppressor of cytokine signaling-2 limits intestinal growth and enterotrophic actions of IGF-I in vivo

Yearbook of Gastroenterology ◽

10.1016/s0739-5930(08)70136-3 ◽

2007 ◽

Vol 2007 ◽

pp. 165-166

Author(s):

M. Osterman

Keyword(s):

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

Intestinal Growth ◽

Igf I

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Distinct mechanisms of induction of hepatic growth hormone resistance by endogenous IL-6, TNF-α, and IL-1β

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00652.2013 ◽

2014 ◽

Vol 307 (2) ◽

pp. E186-E198 ◽

Cited By ~ 23

Author(s):

Yueshui Zhao ◽

Xiaoqiu Xiao ◽

Stuart J. Frank ◽

Herbert Y. Lin ◽

Yin Xia

Keyword(s):

Growth Hormone ◽

Target Gene ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

Gh Receptor ◽

Tnf Α ◽

Igf I ◽

Socs3 Expression ◽

Gh Resistance

During inflammation, the liver becomes resistant to growth hormone (GH) actions, leading to downregulation of the GH target gene IGF-I and activation of catabolism. Proinflammatory cytokines IL-6, TNF-α, and IL-1β are critically involved in the pathogenesis of hepatic GH resistance. However, the mechanisms used by endogenous IL-6, TNF-α, and IL-1β to inhibit the hepatic GH-IGF-I pathway during inflammation are not fully understood. Here, we show that TNF-α and IL-1β inhibited GH receptor (GHR) expression but had minor effects on the downstream suppressor of cytokine signaling (SOCS)3, while IL-6 induced SOCS3 expression but had no effect on GHR expression in Huh-7 cells. Consistent with the in vitro observations, neutralization of TNF-α and IL-1β in mouse models of inflammation did not significantly alter SOCS3 expression stimulated by inflammation but restored GHR and IGF-I expression suppressed by inflammation. Neutralization of IL-6 did not alter inflammation-suppressed GHR expression but drastically reduced the inflammation-stimulated SOCS3 expression and restored IGF-I expression. Interestingly, when the GH-IGF-I pathway was turned off by maximal inhibition of GHR expression, IL-6 and SOCS3 were no longer able to regulate IGF-I expression. Taken together, our results suggest that TNF-α/IL-1β and IL-6 use distinct mechanisms to induce hepatic GH resistance, with TNF-α and IL-1β acting primarily on GHR and IL-6 acting primarily on SOCS3. IL-6 action may be superseded by factors such as TNF-α and IL-1β that inhibit GHR expression.

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