SOCS signaling in autoimmune diseases: Molecular mechanisms and therapeutic implications

Abstract

Suppressor of cytokine signaling (SOCS) proteins are mainly induced by various cytokines and have been described as classical inhibitors of cytokine signaling. SOCS signaling is involved in the regulation of immune cells, and recent findings suggest that SOCS proteins, especially SOCS1 and SOCS3, are often dysregulated in a wide variety of autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, psoriasis, and multiple sclerosis. Recent studies suggest that SOCS signaling could be therapeutically targeted in various autoimmune diseases. In this review, we discuss recent studies on the role of SOCS proteins in the development and pathogenesis of autoimmune diseases, as well as their clinical implications.Keywords: Autoimmune disease r Signaling pathways r Suppressor of cytokine signaling IntroductionCytokines are secreted glycoproteins that regulate diverse physiologic and pathologic responses through their interaction with multisubunit receptor complexes. Receptors of the cytokine superfamily transmit their signaling via intracellular kinases pathways, such as JAK-STAT signaling pathways. Dysregulation of cytokine signaling pathways has been correlated with development and pathogenesis of many autoimmune diseases. Several years ago, the regulators of cytokine pathways called suppressors of cytokine signaling (SOCS) were described [1]. It has been recognized that the expression levels of SOCS are low in the basal state, but are rapidly induced by the JAK-STAT pathway [2]. The upregulated SOCS protein expression in turn triggers a negative feedback process for overactivated cytokine signaling via several inhibitory mechanisms [2]. In this review, we summarize our current underCorrespondence: Prof. Dong-Qing Ye e-mail: ydqahmu@gmail.com standing of the involvement of SOCS proteins in the development and pathogenesis of autoimmune diseases, as well as their clinical implications and novel therapeutic strategies. SOCS protein familyThe SOCS family consists of eight proteins, SOCS1-SOCS7 and CIS, each of which has a central SH2 domain, an amino-terminal domain of varying length and sequence and a carboxy-terminal 40-amino-acid-long module known as the SOCS box [2] (Fig. 1). Cytokine receptor signaling has been found to rapidly induce SOCS protein expression. SOCS proteins are swiftly degraded when cytokine signaling ceases and usually remain inactive in resting cells. Thus, SOCS signaling might have a central role in many immunological processes including immune cell development, differentiation, and function. Although all SOCS proteins share the same basic structure, some intriguing differences among them have been recently recognized. SOCS1 and SOCS3 lack any introns and have an additional domain in their amino-terminal region, which has been named kinase inhibitory region (KIR) [3]. Moreover, SOCS4-SOCS7 exhibit an extended C-terminus [3]. Notably, there are some pairs of SOCS family (CIS and SOCS2; SOCS1 and SOCS3; SOCS4 and SOCS5; and SOCS6 and SOCS7) that display mar...

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“…The SH2-containing STAT1 is subsequently activated by JAK2 and next induces transcription of target genes including those that code profibrotic cytokines (16). The kinase inhibitory region (KIR) of SOCS1 can bind to the loop region of JAK2 and then suppress the JAK catalytic activity, thereby resulting in the inhibition of JAK2 phosphorylation and STAT1 activation (17). …”

Type II SOCS as a feedback repressor for GH-induced Igf1 expression in carp hepatocytes

“…SOCS proteins are widely expressed at tissue level (Delgado-Ortega et al 2011), and their production can be induced by microbial/ viral infection or by cytokine treatment (Hebenstreit et al 2003, Cheng et al 2009). At cellular level, SOCS expression is well documented to serve as the feedback repressor for cytokine signaling via inhibition of JAK/ STAT pathway (Croker et al 2008) and plays a protective role in preventing hyperactivation of immune system, which can lead to autoimmune/inflammatory disorders (Liang et al 2014). In mammals, SOCS proteins can also act as negative modulators for growth hormone (GH) actions (Birzniece et al 2009) and contribute to the cross talk between immune system and somatotropic axis (Ahmed & Farquharson 2010).…”

Suppressor of Cytokine Signaling (SOCS)1 Regulates Interleukin-4 (IL-4)-activated Insulin Receptor Substrate (IRS)-2 Tyrosine Phosphorylation in Monocytes and Macrophages via the Proteasome

“…Dysregulation of SOCS expression has been implicated in several inflammatory diseases, including models of multiple sclerosis (65)(66)(67)(68)(69), rheumatoid arthritis (70,71), systemic lupus erythematosus (72,73), psoriasis (74,75), type 1 diabetes (51, 76 -79), sepsis (80,81), and also in human allergic disease (82)(83)(84). Furthermore, deficiencies in SOCS1 expression have been observed in the smooth muscle in airways (85), and epithelial cells (86) of asthmatic patients and functional SOCS1 polymorphism have been correlated with the development of adult onset asthma and increased IgE levels (87,88).…”