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

• On gestation d 22, SOCS-1 and SOCS-3 mRNA levels were 10-fold that on G20 [10].
• However, the mechanisms underlying SOCS-3 inhibition of IL-1beta signalling and prevention against apoptosis remain unknown [9].
• Increased SOCS-3 expression was preceded by an increase in STAT3 tyrosine phosphorylation 10 min after cloprostenol injection and was maintained for 4 h, as determined by gel shift and immunohistochemistry [11].
• Therefore, induction of SOCS-3 by PGF(2alpha) may be an important element in the initiation of luteolysis via rapid suppression of luteotropic support from PL [11].
• Genes known to be involved in autoimmune response and arthritis, such as those encoding Galectin-3, Versican, and Socs3, were identified and validated by quantitative TaqMan RT-PCR analysis using independent blood samples [12].

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

• Hepatic SOCS-3 expression was only just detectable in the control group but was elevated in all CLP groups and unaffected by nutrition and GH [22].
• SOCS3 may be very important in regulating the balance between immunosuppression and inflammation after thermal injury [23].
• Constitutive activation of STAT-3 and downregulation of SOCS-3 expression induced by adrenalectomy [24].
• By using in situ hybridization, we demonstrated that suppressor of cytokine signaling 3 (SOCS-3) and c-fos mRNAs were significantly induced by the LPS treatment in the anterior lobe of the pituitary [25].

References