SurveyInterleukin-17 family and IL-17 receptors
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.
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TAM and DRH share first authorship.