IL17F (interleukin 17F)

	IL17F gene. The IL17F gene spans a region of 7.86 kb composed of the three exons (untranslated region (UTR), light blue; coding region, red) and two introns (green). Exons 1, 2, and 3 are 141 bp (108 bp 5' UTR plus 33 bp coding region), 221 bp (all coding region), and 488 bp (238 bp coding region plus 250 bp 3' UTR) in length, respectively. The two introns are 5446 bp and 1561 bp in length, respectively.
Description	The gene spans a region of 7857 bases and the coding part is divided into three exons.
Transcription	The 492-nucleotide transcript encodes a protein of 163 amino acid residues. The first and last exons are partially untranslated.
Pseudogene	None described so far.

	Crystal structure of IL-17F at 2.85 A resomution. Adapted from PDB (access number: 1JPY).
Description	Each IL-17F monomer forms homodimer with another IL-17F or heteromer with IL-17A (Chang and Dong, 2007; Wright et al., 2007). Calculated molecular weight of IL-17F monomer is a 15-kD. In non-reducing SDS-PAGE gel, IL-17F homodimer runs between 35 to 50kD depending on the level of glycosylation (Wright et al., 2007).
	IL-17F protein. IL-17F protein (163 amino acids) is composed of a signal peptide (orange, 30 amino acids) and a mature peptide (blue, 133 amino acids). Four conserved cysteine residues form intra-chain disulfide bonds (Cys102/Cys152 and Cys107/Cys154). Other two cysteines (Cys47 and Cys137) participate in homodimer formation via inter-chain disulfide bonds (Hymowitz et al., 2001). There is an intersubunit disulfide linkage between Cys47 from IL-17F and Cys129 from IL-17A. The presence of another intersubunit disulfide bond between Cys137 (IL-17F) and Cys33 (IL-17A) was also reported (Wright et al., 2007).
Expression	Compared to IL-17 expression, IL-17F was detected more broadly in different tissues (Kawaguchi et al., 2001). In lymphoid lineages, IL-17F expression is tightly regulated. Results from IL-17FRFP reporter mouse or intracellular cytokine staining of IL-17F indicate that differentiated CD4 helper T cell Th17 cells, lamina propria CD4 T cells, memory CD4 T cells, γδ T cells, iNKT cells, and innate lymphoid cells (ILC3) produce IL-17F (Cua and Tato, 2010; Pantelyushin et al., 2012; Yang et al., 2008b). Regulation of IL-17F closely resembles its homologous protein IL-17A. In addition to TCR stimulation, TGFβ, IL-6, IL-23 and IL-1β are necessary to shape naïve CD4 T cells to Th17 cells. Transcription factors STAT3 and RORγτ are essential for production of IL-17F as well as IL-17 (Martinez et al., 2008; Peters et al., 2011; Zhou and Littman, 2009). IL-17F expression by either ILC3 or γδ T is induced by IL-1β or IL-23 (Geremia et al., 2011; Sutton et al., 2009). While IL-17A production from iNKT cells is independent from IL-6 (Doisne et al., 2009) and required TGFβ and IL-1β (Monteiro et al., 2013), it is not clear whether IL-17F expression is regulated by the same cytokines in iNKT cells. Distinctive regulatory pathways of IL-17F have been reported. Itk-mediated activation of NFATc1 upon TCR stimulation induces IL-17A but not IL-17F (Gomez-Rodriguez et al., 2009). Conserved noncoding sites (CNS)2 in the Il17-Il17f locus is required for IL-17A expression but partially required for IL-17F expression, indicating other regulatory elements are involved in the regulation of IL-17F expression (Wang et al., 2012). While signaling pathways or transcription factors governing γδ T cells (Korn and Petermann, 2012) or iNKT cells producing IL-17A (Engel et al., 2012; Watarai et al., 2012) were reported before, the specific regulatory pathways of IL-17F in these innate cells remain elusive. IL-17A production is restricted to lymphoid lineages but IL-17F was reported to be expressed by non-lymphoid cells that do not express IL-17A, such as human colonic epithelial cells (Tong et al., 2012). IL-17F is produced by non-T, non-B innate immune cells and mouse colonic epithelial cells in response to infection with C. rodentium (Ishigame et al., 2009). IL-17F is predominantly expressed in bronchial epithelial cells in addition to the infiltrating inflammatory cells upon asthma induction (Suzuki et al., 2007).
Localisation	IL-17F is a secreted protein.
Function	IL-17F exerts its biological effects through the IL-17RA/RC signaling complex. While the expression of IL-17RA is universal, IL-17RC expression is largely restricted to epithelial cells, fibroblasts and other stromal cells. IL-17RA/RC complex recruits an adaptor molecule, Act1, for signaling (Chang et al., 2006; Qian et al., 2007). Upon binding IL-17F, IL-17RA/RC can activate NF-kB and MAPK pathways. IL-17F shares the receptor complex with IL-17A homodimer and IL-17A/F heterodimer. They do not compete for the binding to the receptor complex since these cytokines together in the culture resulted in additive effects on production of pro-inflammatory molecules. Binding affinity of IL-17F to IL-17RA is weaker compared to IL-17F binding to IL-17RC (Kuestner et al., 2007). A crystal structure revealed that IL-17RA bound to IL-17F in a 1:2 stoichiometry and IL-17RA - IL-17F complex prefers to form heterodimers with a second receptor, IL-17RC, possibly due to steric hindrance (Ely et al., 2009).
Homology	IL-17A is the most homologues protein.

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