Perspectives in Diabetes Diabetes and Suppressors of Cytokine Signaling Proteins Sif G. Rønn, 1 Nils Billestrup, 1 and Thomas Mandrup-Poulsen 1,2 T he pathogenesis of type 1 diabetes is not clearly understood, but it is generally accepted that type 1 diabetes is an immune-mediated disease caused 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, CD8 + 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 failure of type 2 diabetes (4). In this review we focus on a group of proteins, the suppressors of cytokine signaling (SOCS), which affect cytokine signaling and appear to play an important role in the pathological processes leading to both type 1 and type 2 diabetes. SOCS PROTEINS The SOCS proteins were identified in 1997 and were characterized as a family of proteins capable of inhibiting Janus kinase (JAK)–signal transducers and activators of transcription (STAT) (JAK-STAT) signaling in various tis- sues (5–7). Eight members of the SOCS family have been identified, SOCS-1–7 and cytokine-inducible SH2-contain- ing protein (CIS) (8). They all contain a conserved COOH- terminal region of 40 amino acids termed the SOCS box (Fig. 1) (5). They have a central SH2 domain, while the NH 2 -terminal region is of variable length with no recogniz- able motif (8). A kinase inhibitory region (KIR) consisting of 12 amino acids is found immediately NH 2 -terminal to the SH2 domain in SOCS-1 and SOCS-3 (9,10). In general, the constitutive level of SOCS protein ex- pression in cells is low, but SOCS protein expression is highly inducible, often in a transient manner, upon stimu- lation with cytokines both in vitro and in vivo (Fig. 2A) (11). IL-1, IFN-, and TNF- can induce SOCS expression in the -cell (12,13). Cytokine-induced SOCS expression is regulated via activation of STAT proteins. STAT-binding elements have been identified in the promoters of CIS (14), SOCS-1 (15), and SOCS-3 (16). Mutations of these ele- ments reduce SOCS expression, and expression of domi- nant-negative variants of the STAT proteins blocks cytokine-induced SOCS expression (7,16,17). 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 and inhibits kinase activity (10). SOCS-3 also inhibits JAK activity, but in contrast to SOCS-1, this requires binding between the SH2 domain of SOCS-3 and the phosphory- lated receptor (9). CIS inhibits cytokine signaling by binding to phosphorylated tyrosine residues on the cyto- kine receptor, thereby masking potential docking sites for downstream signaling molecules such as the STAT pro- teins (18). Finally, SOCS proteins can inhibit signaling by coupling of signaling proteins to degradation via the proteasomal machinery (19). In the context of diabetes, SOCS-1 and -3 are the most relevant SOCS members, and their effects are discussed below. SOCS-2 influences growth hormone effects, and gigantism is seen in mice lacking SOCS-2 (20). Overexpres- FIG. 1. Schematic structure of the SOCS proteins. The SOCS proteins are characterized by a conserved COOH-terminal domain, the SOCS box. Centrally they contain an SH2 domain, while the NH 2 -terminal (N-TERM) region is of variable length and amino acid composition. The kinase inhibitory region (KIR) is only found in SOCS-1 and SOCS-3. From the 1 Steno Diabetes Center, Gentofte, Denmark; and the 2 Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden. Address correspondence and reprint requests to Nils Billestrup, Steno Diabetes Center, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark. E-mail: nbil@steno.dk. Received for publication 1 August 2006 and accepted in revised form 16 November 2006. CIS, cytokine-inducible SH2-containing protein; IL, interleukin; IFN, inter- feron; IRS, insulin receptor substrate; JAK, Janus kinase; MAP, mitogen- activated protein; NF-B, nuclear factor-B; SOCS, suppressors of cytokine signaling; STAT, signal transducers and activators of transcription; TAK-1 kinase, transforming growth factor-–activated kinase; TNF, tumor necrosis factor. DOI: 10.2337/db06-1068 © 2007 by the American Diabetes Association. 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 with 18 U.S.C. Section 1734 solely to indicate this fact. DIABETES, VOL. 56, FEBRUARY 2007 541