Elsevier

Cytokine

Volume 46, Issue 1, April 2009, Pages 7-11
Cytokine

Review Article
IL-17F: Regulation, signaling and function in inflammation

https://doi.org/10.1016/j.cyto.2008.12.024Get rights and content

Abstract

The IL-17 cytokine family is composed of six members. IL-17F, discovered in 2001, recently has drawn increasing attention due to its greatest similarity to IL-17, a widely recognized inflammatory cytokine. The genes encoding IL-17 and IL-17F are localized in the same chromosomal region and are co-expressed by CD4+ and γδ T cells. IL-17F can be secreted as homodimers or heterodimers with IL-17. Similar to IL-17, IL-17F utilizes IL-17RA and IL-17RC as its receptor and employs Act1 and TRAF6 as its signal transducers to induce the expression of pro-inflammatory cytokines and chemokines in many different cell types. However, mice lacking either IL-17 or IL-17F exhibit distinct defects in experimental models of asthma and colitis. These results have laid the basis to understand the role of IL-17F in the pathogenesis of human diseases.

Introduction

The IL-17 family of cytokines contains six members, IL-17 (also called IL-17A), IL-17B, IL-17C, IL-17D, IL-17E (also known as IL-25) and IL-17F. These polypeptides consist of 163–202 amino acids with molecular masses of 20–30 kDa. They share four conserved cysteine residues at C-terminal region that may participate in the formation of intermolecular disulfide linkages [1]. While little is known about IL-17B, IL-17C and IL-17D, IL-25 with least sequence identity with IL-17 has been shown to regulate innate and adaptive allergic responses [2], [3], [4]. On the other hand, IL-17F, the most recently discovered cytokine in this family, shares strongest homology to IL-17 [5], [6].

IL-17 has been associated with the pathogenesis of multiple autoimmune diseases including rheumatoid arthritis, multiple sclerosis and inflammatory bowel diseases [7], [8]. IL-17 also plays a critical role in host defense upon bacterial and fungal infection by recruiting neutrophils and producing antimicrobial-peptide [7]. Recent progress in understanding IL-17 expression and regulation has led to the identification of a new subset of CD4+ helper T (TH) cells, TH17. IL-17F was also found to be co-expressed in TH17 cells [9]. Since many in vitro studies demonstrated that IL-17F has similar proinflammatory function as IL-17, IL-17F may contribute to the host defense and autoimmune function of TH17 cells. In this review, we will summarize the cellular sources, signaling pathways, in vivo and in vitro function of IL-17F based on recent publications.

Section snippets

IL-17F expression and regulation

IL-17F was originally identified in human genome sequence using IL-17 sequence [5], [6]. In addition to activated CD4 T cells, unlike IL-17, IL-17F mRNA was also reported to be associated with activated monocytes, basophils and mast cells [5], [10]. However, cellular sources of IL-17F were revealed by RT-PCR in these reports. Expression of IL-17F at protein levels was not assessed until recently when staining antibody or ELISA became available. When naïve CD4 T cells were activated under TH17

Biological function of IL-17F in vitro

IL-17F, very similar to IL-17, has been considered as an inflammatory cytokine since it induces many proinflammatory cytokines and chemokines. Induction of TGF-β and IL-2 was initially reported in vein endothelial cells, suggesting possible role of IL-17F on angiogenesis [10]. Moreover, IL-17F can also induce ICAM1 and GM-CSF expression in airway bronchial epithelial cells [5], [20]. IL-17F upregulates the expression of IL-6 and CXCL1 in fibroblasts and epithelial cells [11]. CCL2, CCL7, TSLP

Receptors and signaling pathway of IL-17F

In vitro, IL-17F did not bind to purified IL-17RA protein or compete for IL-17 binding to IL-17RA [6]. Blocking IL-17RA using an antibody, however, is sufficient in removing IL-17 signaling but less efficiently for IL-17F [21]. Therefore, it has been speculated that IL-17F also utilizes IL-17RA but with much lower affinity compared to IL-17. Convincing observation was made when IL-17RA-deficient fibroblasts were reported to exhibit impaired responses to IL-17F in producing proinflammatory

Airway inflammation

IL-17F was originally found in bronchoalveolar lavage cells from allergic asthma patients upon ragweed allergen stimulation [5]. In addition, a coding region variant (His161Arg) of IL-17F gene, possibly encoding an antagonist for IL-17F, has been linked to asthma patients in Japanese populations [43]. Therefore, the role of IL-17F in human asthma and airway inflammation is of great interests.

To analyze the function of IL-17F in airway inflammation, adenoviral infection [44] or

Conclusions

Characterization of IL-17 cytokine family members was started with the cytokine IL-17 and now it is extended to IL-17F and IL-25 (IL-17E). IL-17F could be merely deceived as another inflammatory cytokine, whose expression and function overlap with those of IL-17, sharing similar regulation, signaling and functions. However, detailed experimental studies with appropriate tools such as staining antibody and knockout mice have been instrumental in revealing unexpected role of IL-17F in

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