Negative Regulation of Cytokine and TLR Signalings by SOCS and Others

Abstract

This chapter describes two major immune signal pathways, cytokine signaling and toll-like receptor (TLR)-mediated signaling, and also explores the regulatory mechanisms for these pathways, particularly focusing on the family of suppressor of cytokine signaling (SOCS) proteins that is implicated in negative regulation of both cytokine signaling and TLR signaling. Cytokines are important not only for maintenance of homeostasis and defense against microbes, but also the onset and progression of disease. Cytokines signal through their own receptors on the cell surface, most of which lack intrinsic kinase activity but are associated with janus kinases (JAKs), a family of protein tyrosine kinases. Upon ligand binding to cytokine receptors and subsequent receptor dimerization, JAKs are activated to phosphorylate tyrosine residues in the intracellular domain of cytokine receptors. Innate immunity is equipped with various signaling receptors including a TLR family. TLR family consists of more than 10 members, each of which precisely recognizes corresponding molecular patterns associated with pathogens and exerts its host defensive actions based on their ignorance of host-derived intact components. Individual TLRs principally recognize distinct pathogen-associated molecular patterns (PAMPs), which are not expressed on normal mammalian cells. The negative regulation of signal transduction plays a central role in balancing the positive and deleterious consequences of cytokine action. The SOCS proteins are indispensable for regulating many biochemical processes, including leukocyte homeostasis, glucose turnover, cell growth, and responses to pathogens, and are apparently a hallmark of such understanding of cytokine signal regulation.