Review ArticleStructure–function relationships in the IL-17 receptor: Implications for signal transduction and therapy
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.
References (160)
- et al.
Cytokine and cytokine receptor pleiotropy and redundancy
J Biol Chem
(2002) - et al.
Interleukin-17 family and IL-17 receptors
Cytokine Growth Factor Rev
(2003) - et al.
Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17
Immunity
(2005) - et al.
The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses
Immunity
(2003) - et al.
T-cell subsets: the more the merrier
Curr Biol
(2007) - et al.
Differentiation and function of Th17 T cells
Curr Opin Immunol
(2007) - et al.
Th17: an effector CD4 T cell lineage with regulatory T cell ties
Immunity
(2006) - et al.
Interleukin-17 family members and inflammation
Immunity
(2004) - et al.
Identification of an interleukin 17F/17A heterodimer in activated human CD4+ T cells
J Biol Chem
(2007) - et al.
IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo
Immunity
(2001)
The IL-17 cytokine family
The IL-23/Th(17) axis: therapeutic targets for autoimmune inflammation
Curr Opin Immunol
Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor
Immunity
Molecular characterization of the human interleukin-17 receptor
Cytokine
Soluble and transmembrane isoforms of novel interleukin-17 receptor-like protein by RNA splicing and expression in prostate cancer
J Biol Chem
Seeing the light: preassembly and ligand-induced changes of the interferon gamma receptor complex in cells
Mol Cell Proteomics
Three is better than one: pre-ligand receptor assembly in the regulation of TNF receptor signaling
Cytokine
Ligand-induced asymmetry in histidine sensor kinase complex regulates quorum sensing
Cell
The STIR-domain superfamily in signal transduction, development and immunity
Trends Biochem Sci
IL-3, IL-5, and GM-CSF signaling: crystal structure of the human beta-common receptor
Vitam Horm
TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells
Immunity
Functional cooperation between interleukin-17 and tumor necrosis factor-α is mediated by CCAAT/enhancer binding protein family members
J Biol Chem
Interleukin-17 and interferon-γ synergize in the enhancement of proinflammatory cytokine production by human keratinocytes
J Invest Dermatol
IL-17A augments TNF-alpha-induced IL-6 expression in airway smooth muscle by enhancing mRNA stability
J Allergy Clin Immunol
Regulation of granulocyte colony-stimulating factor gene expression by interleukin-17
Immunol Lett
Identification of common transcriptional regulatory elements in interleukin-17 target genes
J Biol Chem
Stimulus-specific induction of a novel nuclear factor-kappaB regulator, IkappaB-zeta, via Toll/Interleukin-1 receptor is mediated by mRNA stabilization
J Biol Chem
T-cell-derived interleukin-17 regulates the level and stability of cyclooxygenase-2 (COX-2) mRNA through restricted activation of the p38 mitogen-activated protein kinase cascade: role of distal sequences in the 3′-untranslated region of COX-2 mRNA
J Biol Chem
Interleukin-17-induced gene expression in articular chondrocytes is associated with activation of mitogen-activated protein kinases and NF-kappaB
J Biol Chem
Interleukin-17 stimulates inducible nitric oxide synthase activation in rodent astrocytes
J Neuroimmunol
IL-17: a prototype member of an emerging family
J Leukoc Biol
T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines
J Exp Med
CD8+ IL-17-producing T cells are important in effector functions for the elicitation of contact hypersensitivity responses
J Immunol
Resident Vdelta1+ gammadelta T cells control early infiltration of neutrophils after Escherichia coli infection via IL-17 production
J Immunol
IL-17 is produced by some proinflammatory Th1/Th0 cells but not by Th2 cells
J Immunol
IL-17 is produced by nickel-specific T lymphocytes and regulates ICAM-1 expression and chemokine production in human keratinocytes: Synergistic or antagonistic effects with IFN-γ and TNF-α
J Immunol
Interleukin 23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin 17
J Biol Chem
Cutting edge: roles of toll-like receptor 4 and IL-23 in IL-17 expression in response to Klebsiella pneumoniae infection
J Immunol
Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation
J Exp Med
Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain
Nature
IL-23 drives a pathogenic T cell population that induces autoimmune inflammation
J Exp Med
IL-12 and IL-23: master regulators of innate and adaptive immunity
Immunol Rev
Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells
Nat Rev Immunol
TGF-beta, a ‘double agent’ in the immune pathology war
Nat Immunol
IL-17 family cytokines and the expanding diversity of effector T cell lineages
Annu Rev Immunol
A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis
J Exp Med
Essential autocrine regulation by IL-21 in the generation of inflammatory T cells
Nature
IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells
Nature
IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways
Nat Immunol
Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides
J Exp Med
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