“Suppressor of Cytokine Signalling” Molecules in Infection and Inflammation

Abstract

Cytokines are messengers that coordinate the development and function of leukocytes and therefore are indispensable for the initiation, maintenance and termination of all types of immune responses. A tight control of cytokine functions is crucial for both, the control of infections and the prevention of infection-associated immunopathology. Different intracellular mechanisms of cytokine signal inhibition are involved in the regulation of innate and adaptive immune responses. Among these, the family of suppressor of cytokine signalling (SOCS) proteins identified more than a decade ago (Endo et al. 1997; Naka et al. 1997; Starr et al. 1997) are non-redundant negative feedback inhibitors of both proinflammatory but also of anti-inflammatory cytokine responses (Kubo et al. 2003; Yoshimura et al. 2007). Type I and type II cytokine receptors do not possess a cytoplasmic kinase activity and therefore are dependent on associated Janus kinases (JAKs). JAKs conduct the signal of many cytokines including many interleukins (IL), all interferons (IFN) and hemopoietins. Activated JAKs cross-phosphorylate themselves and phosphorylate the associated cytokine receptor creating binding sites for proteins that contain phosphotyrosine binding SH2 domains. The SH2 domain of signal transducers and activators of transcription (STATs) then binds to the phosphorylated receptors. Recruited STATs get phosphorylated by the adjacent JAKs, and act as binding sites for the SH2 domain of another STATs, which also will be phosphorylated. The STAT dimer translocates into the nucleus where it acts as a transcription factor activating the transcription of specific genes. The diversity of STATmediated intracellular pathways is due to the presence of 7 STATs, activated by different receptors. Moreover, activated STAT dimers act as homoor heterodimers, which increases the diversity of target promoters and thereby of gene patterns that can be activated. The JAK-STAT pathway can be negatively regulated at different stages: protein tyrosine phosphatases remove phosphates from cytokine receptors and activated STATs, whereas PIAS (protein inhibitors of activated STATs) act in the nucleus (Leonard & O'Shea 1998; Krebs & Hilton 2001; Hebenstreit et al. 2005; Shuai 2006). In this chapter we will focus on the role of another inhibitor of the JAK-STAT pathway, the SOCS proteins. The importance of these proteins is evidenced by the fact that mice deficient for some of the SOCS proteins demonstrated a non-redundant role of SOCS proteins in regulating the immune system (Alexander 2002).