Diabetes and Suppressors of Cytokine Signaling Proteins

  1. Sif G. Rønn1,
  2. Nils Billestrup1 and
  3. Thomas Mandrup-Poulsen12
  1. 1Steno Diabetes Center, Gentofte, Denmark
  2. 2Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden
  1. Address correspondence and reprint requests to Nils Billestrup, Steno Diabetes Center, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark. E-mail: nbil{at}steno.dk

The 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 Langerhans. Infiltrating macrophages release proinflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α, which are toxic to the β-cell. Activated T-cells also produce proinflammatory cytokines such as TNF-α and interferon (IFN)-γ 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 β-cells (1). Type 2 diabetes occurs when β-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 cytokines have also been suggested to contribute to β-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 tissues (5–7). Eight members of the SOCS family have been identified, SOCS-1–7 and cytokine-inducible SH2-containing 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 NH2-terminal region is of variable length with no recognizable motif (8). A kinase inhibitory region (KIR) consisting of 12 amino acids is found immediately NH2-terminal to the SH2 domain in SOCS-1 and SOCS-3 (9 …

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