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Interleukin-17 family and IL-17 receptors

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Abstract

Interleukin-17 (IL-17) is a pro-inflammatory cytokine secreted by activated T-cells. Recently discovered related molecules are forming a family of cytokines, the IL-17 family. The prototype member of the family has been designated IL-17A. Due to recent advances in the human genome sequencing and proteomics five additional members have been identified and cloned: IL-17B, IL-17C, IL-17D, IL-17E and IL-17F. The cognate receptors for the IL-17 family identified thus far are: IL-17R, IL-17RH1, IL-17RL (receptor like), IL-17RD and IL-17RE. However, the ligand specificities of many of these receptors have not been established. The IL-17 signaling system is operative in disparate tissues such as articular cartilage, bone, meniscus, brain, hematopoietic tissue, kidney, lung, skin and intestine. Thus, the evolving IL-17 family of ligands and receptors may play an important role in the homeostasis of tissues in health and disease beyond the immune system. This survey reviews the biological actions of IL-17 signaling in cancers, musculoskeletal tissues, the immune system and other tissues.

Introduction

Interleukin-17 (IL-17A) is a cytokine secreted exclusively by activated T-cells. IL-17 cDNA has been isolated and cloned from the murine hybridomas (cytotoxic T lymphocyte antigen 8 (CTLA-8)) [1], [2] and has homology to open reading frame 13 from the T lymphotropic Herpesvirus saimiri. The human IL-17A gene product is a protein of 150 amino acids with a molecular weight of 15 kDa, and is secreted as a disulfide linked homodimer of 30–35 kDa glycoprotein [3].

Five related cytokines were identified, through database searches and degenerative RT-PCR, that share 20–50% homology to IL-17. IL-17 has been designated IL-17A to indicate that it is the founding member of the IL-17 cytokine family. The shared features of the IL-17 cytokine family include conserved cysteines which, in IL-17F [4], have been shown to exhibit the features of a classic cystine knot structural motif found in bone morphogenetic proteins (BMPs), transforming growth factor beta (TGF-β), nerve growth factor (NGF) and platelet-derived growth factor BB (PDGF-BB) [5]. IL-17F, like IL-17A, is produced primarily in activated T-cells. In contrast, IL-17B, IL-17C, IL-17D, and IL-17E are expressed in a wide assortment of tissues. Their functions partially overlap those of IL-17A, although they have not been as thoroughly investigated.

The receptor for IL-17A (IL-17R) is a single-pass transmembrane protein of approximately 130 kDa. While the IL-17A cytokine is expressed only by T-cells, its receptor is expressed in all tissues examined to date. The activation of the receptor by IL-17A generally results in the induction of other pro-inflammatory cytokines, through the activation of NF-κB.

Four additional receptors have been identified, through database searches, which share partial sequence homology to IL-17R. Of these, only IL-17RH1 (also called IL-17B receptor) has been shown to bind to IL-17 cytokines, namely IL-17B and IL-17E [7], [36]. IL-17 receptor-like protein (also called IL-17RL or IL-17RC), IL-17RD (also called SEF or IL-17RLM) and IL-17RE have only been identified by sequence similarity to IL-17R. Many of these receptors exist as alternatively spliced isoforms, some of which may not contain transmembrane or cytoplasmic domains, and thereby may be acting as soluble decoy receptors. They exhibit a broad tissue distribution, and not much is known about their functions or signal transduction pathways.

With the newly identified family of IL-17 cytokines and receptors, and their expression in disparate tissues, the scope of IL-17 cytokine activity and expression extends beyond the T-cell immune system mediated inflammatory response. IL-17 cytokines and their receptors thus may play an important role in the homeostasis of tissues and the progression of disease.

Section snippets

IL-17 family overview

Proteins with significant homology to IL-17 have been identified recently with the continuing advances and accumulating information in expressed sequence tags (ESTs), genomics and proteomics databases. Some of these cytokines have alternative names as they were originally identified in other systems. These related proteins have been grouped and designated IL-17A–F. Fig. 1 shows an alignment of human IL-17 cytokines, with identical residues darkly shaded and boldface. There are five highly

IL-17 family in cartilage and arthritis

To provide a suitable context for understanding the actions of IL-17 cytokines in cartilage and arthritis, we provide a brief overview of cartilage function and tissue homeostasis.

Articular cartilage is a critical component of diarthroidal joints, providing a low-friction surface for articulation. The major components of cartilage matrix include aggrecan, hyaluronic acid, and type II collagen. Aggrecan is a proteoglycan with many negatively charged glycosaminoglycan (GAG) side chains, which

IL-17 in cancers

The mis-regulation of growth factor pathways is a common feature of many cancers. Although there are no published reports describing genetic linkage of either IL-17 cytokines or receptors directly to cancers, there is evidence that IL-17s are active in cancers. IL-17A has been shown to promote angiogenesis in tumor models and correlates well with the numbers of blood vessels in human ovarian cancers [38]. IL-17A promotes tumorgenicity of human cervical tumors in nude mice and is associated with

IL-17 signaling pathways

The emerging knowledge about the IL-17 family and IL-17 receptors has set the stage for investigation of signaling pathways. IL-17 Receptor (IL-17R) activates extracellular signal-regulated protein kinase (ERK), c-jun N-terminal kinase (JNK) and p38 MAP kinase pathways [13], [21], [44], [45]. These signaling pathways result in up-regulation of IL-6, IL-1 and NF-κB [46]. The current status of the signaling pathways is presented diagrammatically in Fig. 8, and in Table 4. The emerging novel

IL-17 biological activity in other tissues

Interleukin-17 cytokines have been studied in a variety of other tissues and diseases. A large body of evidence shows that IL-17A and IL-17F (ML-1) are involved in asthma. Asthma is marked by the recruitment of neutrophilic leukocytes into the airway, a process thought to be regulated by T-cells through pro-inflammatory cytokines such as IL-6 and TNF-α. IL-17A and IL-17F expression are increased in asthmatic versus normal patients, and both cytokines have been shown to induce IL-6 and IL-8

Acknowledgements

We thank Rita Rowlands for help in the preparation of the manuscript including outstanding bibliographic assistance. Our research is supported by grants from the US Army Medical Research Acquisition Activity (AMRAA), Department of Defense, Award No. DAMD17-02-1-0021; and from the National Institute of Health (NIH), Award No. 1 R01 AR47345-01A2.

References (109)

  • F. Pages et al.

    Control of tumor development by intratumoral cytokines

    Immunol. Lett.

    (1999)
  • F. Benchetrit et al.

    Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism

    Blood

    (2002)
  • S.V. Subramaniam et al.

    Evidence for the involvement of JAK/STAT pathway in the signaling mechanism of interleukin-17

    Biochem. Biophys. Res. Commun.

    (1999)
  • S.V. Subramaniam et al.

    Interleukin-17 induces rapid tyrosine phosphorylation and activation of raf-1 kinase in human monocytic progenitor cell line U937

    Biochem. Biophys. Res. Commun.

    (1999)
  • K. Vuolteenaho et al.

    Effects of TNFalpha-antagonists on nitric oxide production in human cartilage

    Osteoarthritis Cartilage

    (2002)
  • M. Chabaud et al.

    Potential contribution of IL-17-producing Th(1)cells to defective repair activity in joint inflammation: partial correction with Th(2)-promoting conditions

    Cytokine

    (2001)
  • R.L. Van Bezooijen et al.

    Effect of interleukin-17 on nitric oxide production and osteoclastic bone resorption: is there dependency on nuclear factor-kappaB and receptor activator of nuclear factor kappaB (RANK)/RANK ligand signaling?

    Bone

    (2001)
  • Z. Yao et al.

    Herpesvirus saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor

    Immunity

    (1995)
  • J.A. Di Battista et al.

    Suppression of tumor necrosis factor (TNF-alpha) gene expression by prostaglandin E(2). Role of early growth response protein-1 (Egr-1)

    Osteoarthritis Cartilage

    (1999)
  • C.C. Loong et al.

    Expression of interleukin-17 as a predictive parameter in acute renal allograft rejection

    Transplant. Proc.

    (2000)
  • M.A. Antonysamy et al.

    Evidence for a role of IL-17 in alloimmunity: a novel IL-17 antagonist promotes heart graft survival

    Transplant. Proc.

    (1999)
  • M. Kawaguchi et al.

    Activation of extracellular signal-regulated kinase (ERK)1/2, but not p38 and c-Jun N-terminal kinase, is involved in signaling of a novel cytokine, ML-1

    J. Biol. Chem.

    (2002)
  • H.L. Li et al.

    IL-17 and IFN-gamma mRNA expression is increased in the brain and systemically after permanent middle cerebral artery occlusion in the rat

    J. Neuroimmunol.

    (2001)
  • E.E. Moore et al.

    Expression of IL-17B in neurons and evaluation of its possible role in the chromosome 5q-linked form of Charcot-Marie-Tooth disease

    Neuromuscul. Disord.

    (2002)
  • A. Kehlen et al.

    Interleukin-17 stimulates the expression of IkappaB alpha mRNA and the secretion of IL-6 and IL-8 in glioblastoma cell lines

    J. Neuroimmunol.

    (1999)
  • M.B. Teunissen et al.

    Interleukin-17 and interferon-gamma synergize in the enhancement of proinflammatory cytokine production by human keratinocytes

    J. Invest. Dermatol.

    (1998)
  • T. Kinugasa et al.

    Claudins regulate the intestinal barrier in response to immune mediators

    Gastroenterology

    (2000)
  • M. Kawaguchi et al.

    Modulation of bronchial epithelial cells by IL-17

    J. Allergy Clin. Immunol.

    (2001)
  • S. Molet et al.

    IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines

    J. Allergy Clin. Immunol.

    (2001)
  • H. Hoshino et al.

    Increased elastase and myeloperoxidase activity associated with neutrophil recruitment by IL-17 in airways in vivo

    J. Allergy Clin. Immunol.

    (2000)
  • E. Rouvier et al.

    CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a Herpesvirus saimiri gene

    J. Immunol.

    (1993)
  • F. Fossiez et al.

    T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines

    J. Exp. Med.

    (1996)
  • T. Starnes et al.

    Cutting edge: IL-17F, a novel cytokine selectively expressed in activated T cells and monocytes, regulates angiogenesis and endothelial cell cytokine production

    J. Immunol.

    (2001)
  • S.G. Hymowitz et al.

    IL-17s adopt a cystine knot fold: structure and activity of a novel cytokine, IL-17F, and implications for receptor binding

    EMBO J.

    (2001)
  • E. Tian et al.

    Evi27 encodes a novel membrane protein with homology to the IL17 receptor

    Oncogene

    (2000)
  • M. Furthauer et al.

    Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling

    Nat. Cell Biol.

    (2002)
  • M. Tsang et al.

    Identification of Sef, a novel modulator of FGF signalling

    Nat. Cell Biol.

    (2002)
  • M. Ziolkowska et al.

    High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism

    J. Immunol.

    (2000)
  • M. Chabaud et al.

    Enhancing effect of IL-17 on IL-1-induced IL-6 and leukemia inhibitory factor production by rheumatoid arthritis synoviocytes and its regulation by Th2 cytokines

    J. Immunol.

    (1998)
  • M. Chabaud et al.

    Human interleukin-17: a T cell-derived proinflammatory cytokine produced by the rheumatoid synovium

    Arthritis Rheum.

    (1999)
  • L. Rifas et al.

    A novel T cell cytokine stimulates interleukin-6 in human osteoblastic cells

    J. Bone Miner. Res.

    (1999)
  • M. Chabaud et al.

    IL-17 derived from juxta-articular bone and synovium contributes to joint degradation in rheumatoid arthritis

    Arthritis Res.

    (2001)
  • Y. Katz et al.

    Interleukin-17 enhances tumor necrosis factor alpha-induced synthesis of interleukins 1, 6, and 8 in skin and synovial fibroblasts: a possible role as a “fine-tuning cytokine” in inflammation processes

    Arthritis Rheum.

    (2001)
  • J. Martel-Pelletier et al.

    Mitogen-activated protein kinase and nuclear factor kappaB together regulate interleukin-17-induced nitric oxide production in human osteoarthritic chondrocytes: possible role of transactivating factor mitogen-activated protein kinase-activated protein kinase (MAPKAPK)

    Arthritis Rheum.

    (1999)
  • M. Chabaud et al.

    The combination of tumor necrosis factor alpha blockade with interleukin-1 and interleukin-17 blockade is more effective for controlling synovial inflammation and bone resorption in an ex vivo model

    Arthritis Rheum.

    (2001)
  • A. LeGrand et al.

    Interleukin-1, tumor necrosis factor alpha, and interleukin-17 synergistically up-regulate nitric oxide and prostaglandin E2 production in explants of human osteoarthritic knee menisci

    Arthritis Rheum.

    (2001)
  • M.G. Attur et al.

    Interleukin-17 up-regulation of nitric oxide production in human osteoarthritis cartilage

    Arthritis Rheum.

    (1997)
  • E. Lubberts et al.

    IL-4 gene therapy for collagen arthritis suppresses synovial IL-17 and osteoprotegerin ligand and prevents bone erosion

    J. Clin. Invest.

    (2000)
  • E. Lubberts et al.

    Reduction of interleukin-17-induced inhibition of chondrocyte proteoglycan synthesis in intact murine articular cartilage by interleukin-4

    Arthritis Rheum.

    (2000)
  • D.V. Jovanovic et al.

    Stimulation of 92-kd gelatinase (matrix metalloproteinase 9) production by interleukin-17 in human monocyte/macrophages: a possible role in rheumatoid arthritis

    Arthritis Rheum.

    (2000)
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