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Gene Review

Socs3  -  suppressor of cytokine signaling 3

Rattus norvegicus

Synonyms: Cish3, Cytokine-inducible SH2 protein 3, SOCS-3, Socs-3, Ssi-3, ...
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Disease relevance of Socs3

  • Intravenous injection of 20 microgram/kg body weight of CT-1 induced a transient, marked increase in STAT3 activation in various tissues, including heart and lung, and subsequent upregulation of 2 members of the CIS family, JAK-binding protein (JAB)/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3, in the same tissues [1].
  • Considering the ability of these SOCS to inhibit the JAK-STAT pathway induced by GH, these results suggest that the overexpression of SOCS-3 and CIS mRNAs induced by IL-1beta and TNFalpha or by endotoxin in vivo may play a role in the GH resistance induced by sepsis [2].
  • SOCS-3 is a gene up-regulated after ischemia which modulates inflammation by controlling cytokine levels [3].
  • Induction of SOCS-3 followed the cascade of events that take place during the acute phase response and the contribution of IL-6 in activating the inhibitory factor is site specific and not generalized throughout the central nervous system [4].
  • The present data indicate that the JAK/STAT transduction pathways that lead to SOCS-3 transcription are activated within cells accessible from the blood circulation, but not within deep parenchymal elements of the brain during endotoxemia [4].

High impact information on Socs3

  • The expression of the suppressor of cytokine signaling-2 (SOCS-2) was increased twofold in GH-treated CRF animals, and SOCS-3 mRNA levels were elevated by 60% in CRF, independent of GH treatment [5].
  • We conclude that the anorexic and antilipopenic actions of leptin decline with age, possibly through increased SOCS-3 expression, and that this could account for the associated abnormalities in lipid metabolism of the elderly [6].
  • 15d-PGJ2 and rosiglitazone suppress Janus kinase-STAT inflammatory signaling through induction of suppressor of cytokine signaling 1 (SOCS1) and SOCS3 in glia [7].
  • 1Alpha,25-dihydroxyvitamin D3 inhibits GH-induced expression of SOCS-3 and CIS and prolongs growth hormone signaling via the Janus kinase (JAK2)/signal transducers and activators of transcription (STAT5) system in osteoblast-like cells [8].
  • METHODS: The effect of SOCS-3 expression on the global gene-expression profile following IL-1beta exposure was microarray-analysed using a rat beta cell line (INS-1) with inducible SOCS-3 expression [9].

Biological context of Socs3


Anatomical context of Socs3

  • In the present study it is demonstrated that SOCS3 is constitutively expressed at a low level in rat heart and neonatal rat ventricular myocytes [13].
  • CONCLUSIONS/INTERPRETATION: This study suggests that there is an unexpected cross-talk between the SOCS/IFN and the IL-1beta pathways of signalling in pancreatic beta cells, which could lead to a novel perspective of blocking two important proapoptotic pathways in pancreatic beta cells by influencing a single signalling molecule, namely SOCS-3 [9].
  • Immunohistochemistry was used to localize the cellular sites of SOCS-3 and CIS protein expression in the ovary and adrenal gland [14].
  • Northern analysis on whole hypothalamus showed that CIS (cytokine-inducible SH2 domain-containing protein), but not SOCS1 or SOCS3, mRNA expression was significantly (P < 0.01) up-regulated in suckled lactating rats [15].
  • Exercise training increased SOCS-3 mRNA expression by 80% and 154% in the plantaris and soleus muscle, respectively [16].

Associations of Socs3 with chemical compounds

  • Pretreatment of rats with a specific phosphorthioate antisense oligonucleotide to SOCS3, reverses the desensitization to angiotensin signaling, as detected by a fall in c-Jun expression after repetitive infusions of the hormone [13].
  • Thus, SOCS3 is induced by Ang II in rat heart and neonatal rat ventricular myocytes and participates in the modulation of the signal generated by this hormone [13].
  • We also found increased SOCS-3 protein in the ovary by immunoblot and in the corpus luteum by immunohistochemistry [11].
  • The hybridization signal for SOCS-3 messenger RNA was low at 1 h, but robust at 3 and 6 h and declined to return to basal levels 12 h after the single ip LPS injection [4].

Regulatory relationships of Socs3

  • These data suggest that training-induced elevations in SOCS-3 expression in skeletal muscle may contribute to the exercise-induced increase in IL-6 expression through alterations in the mechanisms that mediate NF-kappaB activity [16].
  • On the other hand overexpression of SOCS1 or SOCS3 inhibited both CT-1-induced STAT3 phosphorylation and cell hypertrophy [17].
  • CONCLUSION: The mechanism of growth hormone insensitivity induced by endotoxin was associated with down-regulated GHR mRNA expression at receptor level and up-regulated SOCS-3 mRNA expression at post-receptor level [18].
  • To determine if SOCS-3 gene activity in the hypothalamus could be influenced by changes in physiological levels of circulating leptin, we performed in situ hybridization (ISH) and immunostaining for SOCS-3 expression in fed vs. fasted (48 h) rats [19].

Other interactions of Socs3

  • After induction, SOCS3 associates with JAK2 and impairs further activation of the JAK2/STAT1 pathway [13].
  • Ang II at a physiological concentration enhances the expression of SOCS3 mRNA and protein, mainly via AT1 receptors [13].
  • Although hypothalamic suppressors of cytokine signaling-3 (SOCS3) mRNA levels were increased throughout leptin infusion, SOCS3 protein levels were increased only on d 16 [20].
  • TaqMan analysis of gene expression following chronic FA treatment showed neither a decrease in the amount of leptin receptor (Ob-R) mRNA, nor an increase in the negative regulators of STAT signalling, SOCS3 (suppressors of cytokine signalling) or cytokine inducible sequence (CIS) [21].
  • Exercise increases SOCS-3 expression in rat skeletal muscle: potential relationship to IL-6 expression [16].

Analytical, diagnostic and therapeutic context of Socs3


  1. Induction of JAB/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3 is involved in gp130 resistance in cardiovascular system in rat treated with cardiotrophin-1 in vivo. Hamanaka, I., Saito, Y., Yasukawa, H., Kishimoto, I., Kuwahara, K., Miyamoto, Y., Harada, M., Ogawa, E., Kajiyama, N., Takahashi, N., Izumi, T., Kawakami, R., Masuda, I., Yoshimura, A., Nakao, K. Circ. Res. (2001) [Pubmed]
  2. Potentiation of growth hormone-induced liver suppressors of cytokine signaling messenger ribonucleic acid by cytokines. Colson, A., Le Cam, A., Maiter, D., Edery, M., Thissen, J.P. Endocrinology (2000) [Pubmed]
  3. Gene expression analysis of spontaneously hypertensive rat cerebral cortex following transient focal cerebral ischemia. Raghavendra Rao, V.L., Bowen, K.K., Dhodda, V.K., Song, G., Franklin, J.L., Gavva, N.R., Dempsey, R.J. J. Neurochem. (2002) [Pubmed]
  4. Selective involvement of interleukin-6 in the transcriptional activation of the suppressor of cytokine signaling-3 in the brain during systemic immune challenges. Lebel, E., Vallières, L., Rivest, S. Endocrinology (2000) [Pubmed]
  5. Impaired JAK-STAT signal transduction contributes to growth hormone resistance in chronic uremia. Schaefer, F., Chen, Y., Tsao, T., Nouri, P., Rabkin, R. J. Clin. Invest. (2001) [Pubmed]
  6. The role of leptin resistance in the lipid abnormalities of aging. Wang, Z.W., Pan, W.T., Lee, Y., Kakuma, T., Zhou, Y.T., Unger, R.H. FASEB J. (2001) [Pubmed]
  7. 15d-PGJ2 and rosiglitazone suppress Janus kinase-STAT inflammatory signaling through induction of suppressor of cytokine signaling 1 (SOCS1) and SOCS3 in glia. Park, E.J., Park, S.Y., Joe, E.H., Jou, I. J. Biol. Chem. (2003) [Pubmed]
  8. 1Alpha,25-dihydroxyvitamin D3 inhibits GH-induced expression of SOCS-3 and CIS and prolongs growth hormone signaling via the Janus kinase (JAK2)/signal transducers and activators of transcription (STAT5) system in osteoblast-like cells. Morales, O., Faulds, M.H., Lindgren, U.J., Haldosén, L.A. J. Biol. Chem. (2002) [Pubmed]
  9. Suppressor of cytokine signalling (SOCS)-3 protects beta cells against IL-1beta-mediated toxicity through inhibition of multiple nuclear factor-kappaB-regulated proapoptotic pathways. Karlsen, A.E., Heding, P.E., Frobøse, H., Rønn, S.G., Kruhøffer, M., Orntoft, T.F., Darville, M., Eizirik, D.L., Pociot, F., Nerup, J., Mandrup-Poulsen, T., Billestrup, N. Diabetologia (2004) [Pubmed]
  10. Suppression of Prolactin-Induced Signal Transducer and Activator of Transcription 5b Signaling and Induction of Suppressors of Cytokine Signaling Messenger Ribonucleic Acid in the Hypothalamic Arcuate Nucleus of the Rat during Late Pregnancy and Lactation. Anderson, G.M., Beijer, P., Bang, A.S., Fenwick, M.A., Bunn, S.J., Grattan, D.R. Endocrinology (2006) [Pubmed]
  11. A prostaglandin f(2alpha) analog induces suppressors of cytokine signaling-3 expression in the corpus luteum of the pregnant rat: a potential new mechanism in luteolysis. Curlewis, J.D., Tam, S.P., Lau, P., Kusters, D.H., Barclay, J.L., Anderson, S.T., Waters, M.J. Endocrinology (2002) [Pubmed]
  12. Identification of blood biomarkers of rheumatoid arthritis by transcript profiling of peripheral blood mononuclear cells from the rat collagen-induced arthritis model. Shou, J., Bull, C.M., Li, L., Qian, H.R., Wei, T., Luo, S., Perkins, D., Solenberg, P.J., Tan, S.L., Chen, X.Y., Roehm, N.W., Wolos, J.A., Onyia, J.E. Arthritis Res. Ther. (2006) [Pubmed]
  13. Suppressor of cytokine signaling 3 is induced by angiotensin II in heart and isolated cardiomyocytes, and participates in desensitization. Calegari, V.C., Bezerra, R.M., Torsoni, M.A., Torsoni, A.S., Franchini, K.G., Saad, M.J., Velloso, L.A. Endocrinology (2003) [Pubmed]
  14. Tissue-specific induction of SOCS gene expression by PRL. Tam, S.P., Lau, P., Djiane, J., Hilton, D.J., Waters, M.J. Endocrinology (2001) [Pubmed]
  15. Mechanisms underlying the diminished sensitivity to prolactin negative feedback during lactation: reduced STAT5 signaling and up-regulation of cytokine-inducible SH2 domain-containing protein (CIS) expression in tuberoinfundibular dopaminergic neurons. Anderson, S.T., Barclay, J.L., Fanning, K.J., Kusters, D.H., Waters, M.J., Curlewis, J.D. Endocrinology (2006) [Pubmed]
  16. Exercise increases SOCS-3 expression in rat skeletal muscle: potential relationship to IL-6 expression. Spangenburg, E.E., Brown, D.A., Johnson, M.S., Moore, R.L. J. Physiol. (Lond.) (2006) [Pubmed]
  17. Hypertrophic responses to cardiotrophin-1 are not mediated by STAT3, but via a MEK5-ERK5 pathway in cultured cardiomyocytes. Takahashi, N., Saito, Y., Kuwahara, K., Harada, M., Tanimoto, K., Nakagawa, Y., Kawakami, R., Nakanishi, M., Yasuno, S., Usami, S., Yoshimura, A., Nakao, K. J. Mol. Cell. Cardiol. (2005) [Pubmed]
  18. Mechanism of growth hormone insensitivity induced by endotoxin. Wang, P., Li, N., Li, J.S. Acta Pharmacol. Sin. (2002) [Pubmed]
  19. SOCS-3 expression in leptin-sensitive neurons of the hypothalamus of fed and fasted rats. Baskin, D.G., Breininger, J.F., Schwartz, M.W. Regul. Pept. (2000) [Pubmed]
  20. Leptin signaling in the hypothalamus during chronic central leptin infusion. Pal, R., Sahu, A. Endocrinology (2003) [Pubmed]
  21. Fatty acids inhibit leptin signalling in BRIN-BD11 insulinoma cells. Briscoe, C.P., Hanif, S., Arch, J.R., Tadayyon, M. J. Mol. Endocrinol. (2001) [Pubmed]
  22. Differential expression of suppressors of cytokine signalling genes in response to nutrition and growth hormone in the septic rat. Johnson, T.S., O'Leary, M., Justice, S.K., Maamra, M., Zarkesh-Esfahani, S.H., Furlanetto, R., Preedy, V.R., Hinds, C.J., El Nahas, A.M., Ross, R.J. J. Endocrinol. (2001) [Pubmed]
  23. The effect of burn injury on suppressors of cytokine signalling. Ogle, C.K., Kong, F., Guo, X., Wells, D.A., Aosasa, S., Noel, G., Horseman, N. Shock (2000) [Pubmed]
  24. Constitutive activation of STAT-3 and downregulation of SOCS-3 expression induced by adrenalectomy. Madiehe, A.M., Lin, L., White, C., Braymer, H.D., Bray, G.A., York, D.A. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2001) [Pubmed]
  25. In vivo activation of the interleukin-6 receptor/gp130 signaling pathway in pituitary corticotropes of lipopolysaccharide-treated rats. Gautron, L., Lafon, P., Tramu, G., Layé, S. Neuroendocrinology (2003) [Pubmed]
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