factors other than glucocorticoids are also involved in limiting the stimulation of CRF during stress ( Liu et al . 2006 ). Suppressor of cytokine signaling (SOCS)-3 acts as a potent negative regulator of cytokine signaling ( Krebs & Hilton 2000 ), and is
Kazunori Kageyama, Komaki Hanada, Yasumasa Iwasaki, and Toshihiro Suda
A F Roy, Y Benomar, V Bailleux, C M Vacher, A Aubourg, A Gertler, J Djiane, and M Taouis
pathways ( Bjorbaek et al . 1997 , Bole-Feysot et al . 1998 ). Both pathways induce the expression of suppressor of cytokine signaling 3 (SOCS-3), which is a negative regulator of both hormones ( Ihle 1995 ). We hypothesize that during pregnancy, due to
TS Johnson, M O'Leary, SK Justice, M Maamra, SH Zarkesh-Esfahani, R Furlanetto, VR Preedy, CJ Hinds, AM El Nahas, and RJ Ross
GH treatment during critical illness and sepsis may increase mortality. A family of negative regulators of cytokine signalling, the suppressors of cytokine signalling (SOCS), have been characterised. SOCS provide a mechanism for cross-talk between the cytokine receptors, including GH. Here, we have investigated the impact of nutrition and GH treatment on GH receptor, SOCS1, SOCS-2, SOCS-3 and cytokine-inducible SH2-containing protein (CIS) hepatic mRNA expression in a rat model of sepsis, caecal ligation and puncture (CLP). Four groups of rats were studied: control (food given ad libitum, n=7), CLP only (n=8), CLP and total parenteral nutrition (TPN) (n=9), and CLP, TPN and GH (n=10). CLP rats underwent surgery and 18 h later received saline or TPN or TPN+GH for 6 h before they were killed. Serum IGF-I levels were lower in all CLP groups (P<0.001). The combination of TPN and GH treatment increased IGF-I levels compared with the saline-treated CLP rats (P<0.01), but IGF-I levels remained lower than control animals (P<0.001). GH receptor and GH-binding protein expression in liver was reduced in animals subjected to CLP and was unaffected by nutrition or GH treatment. Hepatic SOCS-1 was detectable in normal rats, induced in all CLP animals but was unaffected by nutrition and GH. Hepatic SOCS-2 expression was difficult to detect in normal and CLP rats but was greatly induced in CLP rats treated with GH. 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. Hepatic CIS expression was difficult to detect in normal rats, was not induced by CLP but was induced by both nutrition and GH. In conclusion, CLP induced low IGF-I levels associated with increased expression of SOCS-1 and SOCS-3, both of which are known to inhibit GH receptor signalling. GH induced SOCS-2 and CIS in the CLP rat despite resistance with respect to IGF-I generation, and parenteral feeding induced CIS in the CLP rat. Thus, there is potential for a complex interaction between GH and cytokine signalling at the level of SOCS expression whereby the inflammatory response may alter GH signalling and GH may influence the inflammatory response.
MA Torsoni, JB Carvalheira, VC Calegari, RM Bezerra, MJ Saad, JA Gontijo, and LA Velloso
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.
M Fasshauer, J Klein, U Lossner, and R Paschke
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.
Xue Jiang, Jia Xiao, Mulan He, Ani Ma, and Anderson O L Wong
Introduction The members of suppressor of cytokine signaling (SOCS) are key regulators of innate ( Strebovsky et al . 2012 ) and adaptive immune systems ( Tamiya et al . 2011 ). In mammals, at least eight members of SOCS family, including
S F Ahmed and C Farquharson
suppressor of cytokine signalling (SOCS) family has been proposed. This review will first describe SOCS proteins and the effects of the GH/insulin-like growth factor 1 (IGF1) axis on linear growth and skeletal development before describing the evidence that
Margaret B Allison and Martin G Myers Jr
activation by JAK2 ( White et al . 1997 , Banks et al . 2000 ). Activated pSTAT3 translocates to the nucleus, where it mediates changes in the expression of target genes, including suppressor of cytokine signaling 3 ( Socs3 ) (which encodes a feedback
M A Hyatt, G S Gopalakrishnan, J Bispham, S Gentili, I C McMillen, S M Rhind, M T Rae, C E Kyle, A N Brooks, C Jones, H Budge, D Walker, T Stephenson, and M E Symonds
changes in abundance of suppressor of cytokine signaling (SOCS) molecules ( Ram & Waxman 1999 ). These pathways are nutritionally sensitive, being down regulated by fasting in 6-week-old rats ( Beauloye et al. 2002 ). However, it is not known whether
M Szczesna, D A Zieba, B Klocek-Gorka, T Misztal, and E Stepien
cellular factors. Recently identified negative inhibitors of cytokine signalling transduction, i.e. suppressors of cytokine signalling (SOCS), can suppress the actions of both PRL ( Bole-Feysot et al . 1998 , Ling & Billig 2001 ) and leptin ( Bjorbaek et