IL17F (interleukin 17F)

2013-09-01   Seon Hee Chang 

Department of Immunology, Center for Inflammation, Cancer, MD Anderson Cancer Center, Houston, TX, USA




Atlas Image
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.


The gene spans a region of 7857 bases and the coding part is divided into three exons.


The 492-nucleotide transcript encodes a protein of 163 amino acid residues. The first and last exons are partially untranslated.


None described so far.


Atlas Image
Crystal structure of IL-17F at 2.85 A resomution. Adapted from PDB (access number: 1JPY).


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).
Atlas Image
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).


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).


IL-17F is a secreted protein.


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).


IL-17A is the most homologues protein.



Familial chronic mucocutaneous candidiasis-6 (CANDF6) is caused by heterozygous ser65-to-leu mutation in the IL17F gene (Puel et al., 2011).
Chronic mucocutaneous candidiasis (CMC) is characterized by infections of the skin, nails, and oral and genital mucosae with Candida albicans, which is commensal in healthy individuals. S65L IL-17F behaves dominant-negative IL17F allele, which impairs the receptor binding and bioactivity of both IL-17F homodimers and IL-17A - IL-17F heterodimers.
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 (Kawaguchi et al., 2006).

Implicated in

Entity name
Host defense against infections
IL-17F expression has been detected in various types of infections. So far, IL-17F has been mainly involved in mucosal host defense mechanisms. IL-17F deficient mice are susceptible in C. rodentium infection and defective in producing β defensin during the infection (Ishigame et al., 2009). IL-17F is also required to protect the mice against mucocutaneous S. aureus infections (Ishigame et al., 2009).
Entity name
Intestinal inflammation
In acute colitis model using dextran sulfate sodium, IL-17F deficiency resulted in reduced colitis symptoms (Yang et al., 2008a). This phenotype is opposite to IL-17 deficiency, where IL-17 knockout mice developed more severe colitis. However, in chronic colitis using CD4 transfer system, pathology was mediated by redundant effects of IL-17A and IL-17F (Leppkes et al., 2009), suggesting therapeutic blocking of both IL-17A and IL-17F is likely to be required to suppress the inflammation in colon.
Entity name
Colon cancer
IL-17F deficiency resulted in increased colonic tumor numbers. IL-17F is expressed in normal human colonic epithelial cells, but this expression is greatly decreased in colon cancer tissues in this study (Tong et al., 2012).
Entity name
Autoimmune diseases
In experimental autoimmune encephalitis, IL-17F is not required for the initiation of the disease (Yang et al., 2008a) and may play a redundant role in promoting inflammation (Haak et al., 2009). IL-17F is not required to induce inflammation either in collagen induced arthritis model, or arthritis model using IL-1rn deficient mice (Ishigame et al., 2009).
Entity name
Lung inflammations
IL-17F has been detected in the lungs from asthma and COPD. IL-17F was detected in BALF of allergic patients (Kawaguchi et al., 2001) or bronchial epithelial cells after asthma induction (Suzuki et al., 2007). The role of IL-17F in allergic asthma has been argued. While several studies have shown that IL-17A and IL-17F are dispensable or negative regulator in eosinophilia of allergic asthma (Schnyder-Candrian et al., 2006; Suzukawa et al., 2012), asthmatic inflammation is heterogeneous. Steroid-resistant airway inflammation, airway remodeling, or airway hyperreactivity during asthmatic inflammation were reported to be dependent on Th17 or IL-17A (Kudo et al., 2012; Lajoie et al., 2010; McKinley et al., 2008; Pichavant et al., 2008). IL-17F, on the other hand, was required for neutrophil recruitment upon acute allergen challenge (Yang et al., 2008a).


Pubmed IDLast YearTitleAuthors
174529982007A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses.Chang SH et al
170352432006Act1 adaptor protein is an immediate and essential signaling component of interleukin-17 receptor.Chang SH et al
205593262010Innate IL-17-producing cells: the sentinels of the immune system.Cua DJ et al
195870132009Skin and peripheral lymph node invariant NKT cells are mainly retinoic acid receptor-related orphan receptor (gamma)t+ and respond preferentially under inflammatory conditions.Doisne JM et al
198381982009Structural basis of receptor sharing by interleukin 17 cytokines.Ely LK et al
230342802012The transcription factor Th-POK negatively regulates Th17 differentiation in Vα14i NKT cells.Engel I et al
215763832011IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease.Geremia A et al
198186502009Differential expression of interleukin-17A and -17F is coupled to T cell receptor signaling via inducible T cell kinase.Gomez-Rodriguez J et al
190753952009IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice.Haak S et al
115744642001IL-17s adopt a cystine knot fold: structure and activity of a novel cytokine, IL-17F, and implications for receptor binding.Hymowitz SG et al
191443172009Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses.Ishigame H et al
166309362006IL-17F sequence variant (His161Arg) is associated with protection against asthma and antagonizes wild-type IL-17F activity.Kawaguchi M et al
222397192012Development and function of interleukin 17-producing γδ T cells.Korn T et al
223880912012IL-17A produced by αβ T cells drives airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contraction.Kudo M et al
179116332007Identification of the IL-17 receptor related molecule IL-17RC as the receptor for IL-17F.Kuestner RE et al
208024842010Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma.Lajoie S et al
189927452009RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F.Leppkes M et al
190763512008Regulation and function of proinflammatory TH17 cells.Martinez GJ et al
187688652008TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice.McKinley L et al
232933592013Induced IL-17-producing invariant NKT cells require activation in presence of TGF-β and IL-1β.Monteiro M et al
225468552012Rorγt+ innate lymphocytes and γδ T cells initiate psoriasiform plaque formation in mice.Pantelyushin S et al
218999972011The many faces of Th17 cells.Peters A et al
182501912008Ozone exposure in a mouse model induces airway hyperreactivity that requires the presence of natural killer T cells and IL-17.Pichavant M et al
213501222011Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity.Puel A et al
172777792007The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease.Qian Y et al
171017342006Interleukin-17 is a negative regulator of established allergic asthma.Schnyder-Candrian S et al
196829292009Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity.Sutton CE et al
229424222012Epithelial cell-derived IL-25, but not Th17 cell-derived IL-17 or IL-17F, is crucial for murine asthma.Suzukawa M et al
175412852007Expression of interleukin-17F in a mouse model of allergic asthma.Suzuki S et al
225093712012A protective role by interleukin-17F in colon tumorigenesis.Tong Z et al
222448452012Transcription of Il17 and Il17f is controlled by conserved noncoding sequence 2.Wang X et al
223467322012Development and function of invariant natural killer T cells producing T(h)2- and T(h)17-cytokines.Watarai H et al
173559692007Identification of an interleukin 17F/17A heterodimer in activated human CD4+ T cells.Wright JF et al
184113382008Regulation of inflammatory responses by IL-17F.Yang XO et al
185850652008Molecular antagonism and plasticity of regulatory and inflammatory T cell programs.Yang XO et al
193286692009Transcriptional regulatory networks in Th17 cell differentiation.Zhou L et al

Other Information

Locus ID:

NCBI: 112744
MIM: 606496
HGNC: 16404
Ensembl: ENSG00000112116


dbSNP: 112744
ClinVar: 112744
TCGA: ENSG00000112116


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Cytokine-cytokine receptor interactionKEGGko04060
Cytokine-cytokine receptor interactionKEGGhsa04060
Inflammatory bowel disease (IBD)KEGGhsa05321
Inflammatory bowel disease (IBD)KEGGko05321
Immune SystemREACTOMER-HSA-168256
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-17 signalingREACTOMER-HSA-448424
Th17 cell differentiationKEGGko04659
Th17 cell differentiationKEGGhsa04659
Interleukin-4 and 13 signalingREACTOMER-HSA-6785807
IL-17 signaling pathwayKEGGko04657
IL-17 signaling pathwayKEGGhsa04657


Pubmed IDYearTitleCitations
159726742005Role of IL-17A, IL-17F, and the IL-17 receptor in regulating growth-related oncogene-alpha and granulocyte colony-stimulating factor in bronchial epithelium: implications for airway inflammation in cystic fibrosis.145
180880642008Role of the novel Th17 cytokine IL-17F in inflammatory bowel disease (IBD): upregulated colonic IL-17F expression in active Crohn's disease and analysis of the IL17F p.His161Arg polymorphism in IBD.98
180880642008Role of the novel Th17 cytokine IL-17F in inflammatory bowel disease (IBD): upregulated colonic IL-17F expression in active Crohn's disease and analysis of the IL17F p.His161Arg polymorphism in IBD.98
241203612013An ACT1 mutation selectively abolishes interleukin-17 responses in humans with chronic mucocutaneous candidiasis.93
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
186849712008The human IL-17F/IL-17A heterodimeric cytokine signals through the IL-17RA/IL-17RC receptor complex.77
166309362006IL-17F sequence variant (His161Arg) is associated with protection against asthma and antagonizes wild-type IL-17F activity.60
198381982009Structural basis of receptor sharing by interleukin 17 cytokines.58
232385592013Neutrophils, neutrophil extracellular traps and interleukin-17 associate with the organisation of thrombi in acute myocardial infarction.45
178286182008The influence of polymorphisms of interleukin-17A and interleukin-17F genes on the susceptibility to ulcerative colitis.36


Seon Hee Chang

IL17F (interleukin 17F)

Atlas Genet Cytogenet Oncol Haematol. 2013-09-01

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