Elsevier

Cytokine

Volume 41, Issue 2, February 2008, Pages 92-104
Cytokine

Review Article
Structure–function relationships in the IL-17 receptor: Implications for signal transduction and therapy

https://doi.org/10.1016/j.cyto.2007.11.013Get rights and content

Abstract

IL-17 is the defining cytokine of a newly-described “Th17” population that plays critical roles in mediating inflammation and autoimmunity. The IL-17/IL-17 receptor superfamily is the most recent class of cytokines and receptors to be described, and until recently very little was known about its function or molecular biology. However, in the last year important new insights into the composition and dynamics of the receptor complex and mechanisms of downstream signal transduction have been made, which will be reviewed here.

Section snippets

Introduction: A unique subset of Th cells produce IL-17

Cytokines coordinate nearly all immune functions, as well as many other processes such as bone remodeling, mammary gland development and nervous system function. A cytokine’s function is determined by its cognate receptor’s molecular signals, and receptor structure is, generally speaking, predictive of signaling function. For this reason, cytokines have been divided into a limited number of families based primarily on structural features of their receptors [1]. The newest grouping to be

The IL-17 and IL-17R superfamily

Six IL-17-family ligands in mammalian cells and one virally-encoded ligand have been described, and five related receptors have been identified (Table 1). The best characterized ligand is IL-17 (CTLA-8, IL-17A) [31]. IL-17F is the most closely-related protein, with ∼60% homology to IL-17 [32]. Although distinct in primary sequence, IL-17F was found to be structurally similar to cysteine knot cytokines such as PDGF and NGF, and models of IL-17 indicate it adopts a similar three-dimensional

Anti-cytokine therapy and the IL-17R complex

Antibodies and soluble decoy cytokine receptors are currently used to treat RA, Crohn’s disease and other inflammatory conditions [45]. Inflammatory cytokines such as TNFα, IL-β and IL-6 are the major targets of current anti-cytokine therapies. However, none of these drugs are successful in all patients [45], [46]. The pathogenic role of IL-17 in autoimmunity and its functional similarities to TNFα and IL-1β makes this cytokine/receptor system an attractive drug target [47], but little is

Structural features of the IL-17RA extracellular domain: receptor pre-assembly

All known cytokine receptors are multimeric, and oligomerization of receptor subunits is essential for activating signal transduction. For many years the paradigm for cytokine receptor signaling was that individual subunits exist as monomers in the plasma membrane, and ligand causes receptor subunits to oligomerize and thereby initiate signaling by bringing appropriate enzymes or adaptors into proximity. However, in most situations where this has been examined closely, this model has been

IL-17R signal transduction

Much is now known regarding IL-17 and IL-17RA function, but our understanding of IL-17 receptor signal transduction is still surprisingly limited. As indicated, the IL-17RA bears little homology to other known cytokine receptor families [48], [69]. Since there was no obvious model based on homologous receptors, efforts were made to understand IL-17RA signal transduction from the “bottom up,” based on IL-17 target genes and their promoters. The following sections describe the major categories of

Acknowledgments

S.L.G. was supported by the NIH (AI43929) and the Arthritis Foundation. We thank Drs. Reen Wu (UC Davis, Davis CA), Steven Levin (Zymogenetics, Seattle WA), Pamela Ohashi (U. Toronto, Toronto Canada), Wen-Chen Yeh (Amgen, Thousand Oaks, CA) and Wenjun Ouyang (Genentech, South San Francisco, CA) for sharing unpublished information.

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