Perspectives in Diabetes Diabetes and Suppressors of Cytokine Signaling Proteins Sif G
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Perspectives in Diabetes Diabetes and Suppressors of Cytokine Signaling Proteins Sif G. Rønn,1 Nils Billestrup,1 and Thomas Mandrup-Poulsen1,2 he pathogenesis of type 1 diabetes is not clearly understood, but it is generally accepted that type 1 diabetes is an immune-mediated disease Tcaused by inflammation in the islets of Langer- hans. Infiltrating macrophages release proinflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-␣, which are toxic to the -cell. Activated T-cells also produce proinflammatory cytokines such as TNF-␣ and interferon (IFN)-␥ and express the apoptosis- inducing protein FasL. Moreover, CD8ϩ T-cells induce cell death via the perforin-granzyme pathway. The net effect of these different factors results in specific destruction of the insulin-producing -cells (1). Type 2 diabetes occurs when -cell secretory capacity fails to compensate for insulin resistance. In type 2 diabetes, cytokines are known to be involved in insulin and leptin resistance (2,3), and cyto- kines have also been suggested to contribute to -cell FIG. 1. Schematic structure of the SOCS proteins. The SOCS proteins failure of type 2 diabetes (4). are characterized by a conserved COOH-terminal domain, the SOCS box. Centrally they contain an SH2 domain, while the NH2-terminal In this review we focus on a group of proteins, the (N-TERM) region is of variable length and amino acid composition. The suppressors of cytokine signaling (SOCS), which affect kinase inhibitory region (KIR) is only found in SOCS-1 and SOCS-3. cytokine signaling and appear to play an important role in the pathological processes leading to both type 1 and type 2 diabetes. of 12 amino acids is found immediately NH2-terminal to the SH2 domain in SOCS-1 and SOCS-3 (9,10). In general, the constitutive level of SOCS protein ex- SOCS PROTEINS pression in cells is low, but SOCS protein expression is The SOCS proteins were identified in 1997 and were highly inducible, often in a transient manner, upon stimu- characterized as a family of proteins capable of inhibiting lation with cytokines both in vitro and in vivo (Fig. 2A) Janus kinase (JAK)–signal transducers and activators of (11). IL-1, IFN-␥, and TNF-␣ can induce SOCS expression transcription (STAT) (JAK-STAT) signaling in various tis- in the -cell (12,13). Cytokine-induced SOCS expression is sues (5–7). Eight members of the SOCS family have been regulated via activation of STAT proteins. STAT-binding identified, SOCS-1–7 and cytokine-inducible SH2-contain- elements have been identified in the promoters of CIS (14), ing protein (CIS) (8). They all contain a conserved COOH- SOCS-1 (15), and SOCS-3 (16). Mutations of these ele- ϳ terminal region of 40 amino acids termed the SOCS box ments reduce SOCS expression, and expression of domi- (Fig. 1) (5). They have a central SH2 domain, while the nant-negative variants of the STAT proteins blocks NH2-terminal region is of variable length with no recogniz- cytokine-induced SOCS expression (7,16,17). able motif (8). A kinase inhibitory region (KIR) consisting SOCS-mediated downregulation of cytokine-induced JAK-STAT signaling involves different mechanisms (Fig. 2B). Via its SH2 domain, SOCS-1 binds directly to the JAK From the 1Steno Diabetes Center, Gentofte, Denmark; and the 2Department of and inhibits kinase activity (10). SOCS-3 also inhibits JAK Molecular Medicine, Karolinska Institute, Stockholm, Sweden. activity, but in contrast to SOCS-1, this requires binding Address correspondence and reprint requests to Nils Billestrup, Steno between the SH2 domain of SOCS-3 and the phosphory- Diabetes Center, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark. E-mail: [email protected]. lated receptor (9). CIS inhibits cytokine signaling by Received for publication 1 August 2006 and accepted in revised form 16 binding to phosphorylated tyrosine residues on the cyto- November 2006. kine receptor, thereby masking potential docking sites for CIS, cytokine-inducible SH2-containing protein; IL, interleukin; IFN, inter- feron; IRS, insulin receptor substrate; JAK, Janus kinase; MAP, mitogen- downstream signaling molecules such as the STAT pro- activated protein; NF-B, nuclear factor-B; SOCS, suppressors of cytokine teins (18). Finally, SOCS proteins can inhibit signaling by signaling; STAT, signal transducers and activators of transcription; TAK-1 coupling of signaling proteins to degradation via the kinase, transforming growth factor-–activated kinase; TNF, tumor necrosis proteasomal machinery (19). factor. DOI: 10.2337/db06-1068 In the context of diabetes, SOCS-1 and -3 are the most © 2007 by the American Diabetes Association. relevant SOCS members, and their effects are discussed The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance below. SOCS-2 influences growth hormone effects, and with 18 U.S.C. Section 1734 solely to indicate this fact. gigantism is seen in mice lacking SOCS-2 (20). Overexpres- DIABETES, VOL. 56, FEBRUARY 2007 541 DIABETES AND SOCS PROTEINS FIG. 2. The SOCS proteins inhibit cytokine signaling. A: Cytokine-induced activation of the JAK-STAT pathway results in expression of the various SOCS proteins. B: Following, the SOCS proteins downregulate cytokine signaling in different ways. SOCS-1 binds to and inhibits JAK-activity. SOCS-3 binds the phosphorylated (P) cytokine receptor and inhibits JAK activity. CIS binds the receptor, thereby masking STAT docking sites. Finally, via their SOCS box, all SOCS proteins may target their bound signaling molecules for ubiquitination (Ub) and degradation via the proteasomal complex. sion and knock-out studies have revealed sparse informa- A central component in the IL-1–induced signaling tion on CIS and SOCS-4–7; however, it seems as though pathway is the transforming growth factor-–activated both SOCS-6 and -7 are involved in suppression of insulin kinase (TAK-1), as this enzyme is required for activation of signaling (21–23). the MAP kinase and NF-B signaling pathways induced by IL-1 (Fig. 3). In addition to NF-B, SOCS-3 also inhibits SOCS PROTEINS AND INFLAMMATION IL-1–induced activation of the MAP kinases JNK and p38 Since the SOCS proteins were discovered based on their (27). SOCS-3 inhibits IL-1 signaling at the level of the ability to suppress JAK-STAT signaling, we and others TAK-1 kinase by interfering with the interaction between investigated whether these proteins were able to suppress TAK-1 and TRAF-6, an interaction essential for TAK-1 signaling induced by cytokines in -cells, as this might activation (Fig. 3) (27). prove to be a new target of -cell protection. IFN-␥ Taken together, expression of SOCS-3 in -cells leads to signaling through activation of the JAK-STAT pathway has a prevention of -cell destruction upon cytokine exposure previously been shown to be one of the classical targets of due to reduced NF-B and MAP kinase activation and a SOCS-mediated cytokine inhibition, and indeed, we found reduction in NO production (and probably caspase activa- that SOCS-3 could inhibit IFN-␥ signaling in the -cell line tion), thereby preventing cell necrosis and/or apoptosis. INS-1 (24). Similarly, SOCS-1 has been shown to suppress Array analysis suggested that SOCS-3 inhibits IL-1–in- IFN-␥ signaling in the -cell (25,26). In addition to IFN-␥ duced activation of genes involved in the immune/inflam- signaling, SOCS-3 also suppresses IL-1 signaling in the matory response such as intracellular adhesion molecule -cell, an unexpected finding, as this cytokine induces and proteasome and complement components and chemo- activation of mainly nuclear factor-B (NF-B) and mito- kines (28) along with genes involved in apoptosis, for gen-activated protein (MAP) kinases, demonstrating a example the oncogene c-myc, which has been shown to novel mode of action of the SOCS proteins (27). cause apoptosis of -cells in RIP-II/c-myc transgenic mice NF-B is generally involved in cell-survival pathways, (28,29). and indeed the exposure of -cells to IL-1 activates both Because SOCS proteins can protect -cells in vitro, it is cell protective and deleterious mechanisms. However, in obvious to hypothesize a protective effect of SOCS expres- the -cell the protective response is probably not sufficient sion against diabetes development in vivo, and SOCS-1 has to overcome the destructive mechanisms, and eventually been exploited in this particular context. The T-cell recep- apoptosis is induced (1). Numerous IL-1–induced NF-B– tor transgenic NOD8.3 mouse is a simple diabetes model in dependent genes, both proapoptotic such as inducible which CD8ϩ T-cell mediated -cell death can be studied nitric oxide synthase (iNOS) and antiapoptotic such as (30). When SOCS-1 is overexpressed in -cells in these manganese superoxide dismutase (MnSOD), are down- mice (RIP-SOCS-1/NOD8.3), diabetes development is com- regulated upon SOCS-3 overexpression in the -cell (28), pletely prevented. Inflammation of the islets is not affected suggesting that SOCS-3 influences NF-B activity. SOCS-3 in this model, indicating that SOCS-1 inhibits the effector inhibits IL-1–induced NF-B DNA binding as well as pathways activated by the 8.3 T-cells in -cells, e.g., IL-1–induced activation of NF-B–dependent gene tran- TNF-␣– and IFN-␥–induced Fas expression (31). NOD scription. In addition, SOCS-3 prevents IL-1–induced IB mice with -cell–specific overexpression of SOCS-1 have a degradation (28). Despite the inhibitory effect on both pro- reduced incidence of diabetes (26,31), correlating with a and antiapoptotic pathways, SOCS expression protects the decreased IFN-␥–induced STAT-1 activation in the SOCS- -cells against the toxic effect of IL-1.