Introduction

Interleukin-10 (IL-10) is a pleiotropic cytokine produced by activated T cells, B cells, monocytes/macrophages, mast cells and keranocytes (reviewed in ref. 1). IL-10 was first recognized as a cytokine synthesis inhibitory factor1-3 due to its ability to suppress macrophages, inhibiting production of a number of cytokines, and an ability to serve as accessory cells for stimulation of T cell and natural killer cell function.4-7 It also exhibits some stimulatory activity for proliferation and differentiation of B cells, mast cells, and T cells.8 Biologically functional human IL-10 is a 36 kDa dimer1,9,10 consisting of two 160 amino acid residue long polypeptide chains. In order to initiate signal transduction, IL-10 requires two receptor chains, IL-10R111 and IL-10R2.12 Both chains contain extracellular, transmembrane and intracellular domains, and belong to class II or interferon receptor family.13,14 That family is characterized by the presence of two particular disulfide bridges and the absence of the so called "WSXWS motif" in the C-terminal part of the extracellular domain.

A number of viral and cellular gene homologs of IL-10 have been discovered recently.15-17 Viral homologs were found in the Epstein-Barr virus18-20 (EBV), equine herpesvirus type 2,21 Orf parapoxvirus,22,23 human and simian cytomegaloviruses (CMV),24,25 and Yaba-like disease

Interleukin-10, edited by Francesco M. Marincola. ©2006 Eurekah.com.

Figure 1A. Stereo ribbon diagram of the monomer of IL-10, hydrophobic residues are shown in red, all others in green, disulfide bridges are in yellow, helices are labeled A-F.

virus.26 Although the amino acid identity of these proteins with human IL-10 varies between 23% to 85%, they all use IL-10 receptor system, and, as shown by crystal structures of EBV and CMV IL-10s,27,28 they are very likely to be a dimers having three dimensional structures similar to that of IL-10. Cellular homologs include IL-19,29 IL-20,30 IL-22,3132 IL-24,33 IL-26;34 all have much lower amino acid sequence similarity with the human IL-10. Most of them are monomers having structures somewhat similar to the structure of a domain of IL-10;35,36 the only exception is IL-26, which is likely a dimer.

This chapter describes three-dimensional structure of human IL-10, the interactions of this cytokine with the extracellular domain of IL-10R1 receptor, and possible stoichiometry of the signaling ternary complex.

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