Biology:IL17F

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Interleukin 17F (IL-17F) is signaling protein that is in human encoded by the IL17F gene and is considered a pro-inflammatory cytokine. This protein belongs to the family of interleukin 17 and is mainly produced by the T helper 17 cells after their stimulation with interleukin 23. However, IL-17F can be also produced by a wide range of cell types, including innate immune cells and epithelial cells.[1][2][3][4]

The IL17F gene is located on chromosome 6p12 and was discovered in 2001. This cytokine can be secreted as disulfide-linked homodimer or heterodimer.[5][6]

Function and signaling

IL-17F is involved in the development of inflammation and host defense against infection by inducing the expression of genes that encode other proinflammatory cytokines, such as: tumor necrosis factor, interleukin 1, interleukin 6 and some members of the family of colony-stimulating factors. IL-17F can also induce expression of chemokines, such as: CXCL1, CXCL5, interleukin 8, CCL7 and others thereby promote inflammation and neutrophil recruitment. IL-17F signaling can also lead to antimicrobial peptides and matrix metalloproteinases production. The target cells of IL-17F are epithelial cells, fibroblasts, keratinocytes, synoviocytes and endothelial cells. These cells express IL-17RA and IL-17RC which are the receptors IL-17F utilizes. IL-17F shows a wide tissue expression pattern including lung which may be associated with the pathogenesis of asthma. IL-17F employs Act1 and TRAF6 as its signal transducers to induce the expression of the pro-inflammatory cytokines and chemokines in many different cell types. IL-17F signaling in cells also activates the MAP kinase related pathway and leads to the activation of NF-kB, MAPK-AP-1 and C/EBP.[3][5][7]

IL-17F is highly homologous (55%) to interleukin-17A (IL-17A), these two molecules even bind to the same receptor and they are very likely to have similar biological functions. IL-17A and IL-17F are often co-expressed. However, IL-17F is a weaker inducer of pro-inflammatory cytokine expression and is produced by a wider range of cell types compared to IL-17A. Another difference are the different binding affinities of IL-17A and IL-17F for their receptor.[3][8][9]

The family of interleukin 17 belongs to the effector cytokines of Th17 immune response. This immune response protects hosts from pathogens at epithelial and mucosal tissues including the skin, lung, and intestine. The Th17-type immune response is directed primarily against extracellular bacteria. IL-17F as an effector cytokine of Th17 cells is involved in host defense against bacterial infections. It has many mechanisms how to resist bacteria. IL-17F has the ability to product defensins and other antimicrobial peptides, it can also resist bacteria through production of pro-inflammatory cytokines and chemokines that attract neutrophils and other effector cells.[3][10]

Clinical significance

IL-17F is associated as a proinflammatory cytokine with many diseases. It very often plays crucial role in autoimmune diseases.

One of the diseases associated with IL-17F is psoriasis. IL-17F was originally found in bronchoalveolar lavage cells from allergic asthma patients upon ragweed allergen stimulation. Levels of IL-17F, as well as the levels of IL-17A, are increased in psoriatic skin and synovial cell in psoriatic arthritis. IL-17F is capable of to induce significant cartilage matrix release and can inhibit the synthesis of new cartilage matrix. As a result, a monoclonal antibody against IL-17A and IL-17F was created. This antibody is known as Bimekizumab and could be used in psoriasis and also ankylosing spondylitis treatment.[11][12]

IL-17F plays an important role in asthma due to its pro-inflammatory function. IL-17F has been well characterized both in vitro and in vivo and has been shown to have a pro-inflammatory role in asthma. Expression level of IL-17F correlates with a severity of the disease. Overexpression of this cytokine in the airway is associated with neutrophilia, secretion of many cytokines, increased airway activity and mucus hypersecretion. These mechanisms suggest a crucial role of IL-17F in asthma and allergic airway inflammation.[5]

IL-17F was also shown to be involved in pathogenesis of intestinal inflammation. Expression of IL-17F in colon is associated with inflammatory bowel disease (IBD) and this inducible IL-17F expression is significantly higher in Crohn’s disease as compared with ulcerative colitis.[7][12]

Increased expression of IL-17F was also found in neuronal inflammation, specifically in active lesion sites in experimental autoimmune encephalitis (EAE), an animal model of multiple sclerosis. IL-17F together with IL-17A contributes to chronic inflammation.[12]

IL-17F may also be involved in tumorigenesis and associated with tumor microenvironment (TME) based on the pro-tumor and anti-tumor function of IL-17A. However, the role of IL-17F in tumor development have not been well described, their potential contributions deserve consideration, particularly in light of their distinct expression profiles.[3]

References

  1. ↑ Linares-Pineda, Teresa María; Cañadas-Garre, Marisa; Sánchez-Pozo, Antonio; Calleja-Hernández, Miguel Ángel (November 2016). "Gene polymorphisms as predictors of response to biological therapies in psoriasis patients" (in en). Pharmacological Research 113: 71–80. doi:10.1016/j.phrs.2016.07.020. https://linkinghub.elsevier.com/retrieve/pii/S104366181630648X. 
  2. ↑ Moseley, T.A.; Haudenschild, D.R.; Rose, L.; Reddi, A.H. (April 2003). "Interleukin-17 family and IL-17 receptors" (in en). Cytokine & Growth Factor Reviews 14 (2): 155–174. doi:10.1016/S1359-6101(03)00002-9. https://linkinghub.elsevier.com/retrieve/pii/S1359610103000029. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Iwakura, Yoichiro; Ishigame, Harumichi; Saijo, Shinobu; Nakae, Susumu (February 2011). "Functional Specialization of Interleukin-17 Family Members" (in en). Immunity 34 (2): 149–162. doi:10.1016/j.immuni.2011.02.012. https://linkinghub.elsevier.com/retrieve/pii/S1074761311000501. 
  4. ↑ McGeachy, Mandy J.; Cua, Daniel J.; Gaffen, Sarah L. (April 2019). "The IL-17 Family of Cytokines in Health and Disease" (in en). Immunity 50 (4): 892–906. doi:10.1016/j.immuni.2019.03.021. PMID 30995505. PMC 6474359. https://linkinghub.elsevier.com/retrieve/pii/S1074761319301384. 
  5. ↑ 5.0 5.1 5.2 Kawaguchi, Mio; Kokubu, Fumio; Fujita, Junichi; Huang, Shau-Ku; Hizawa, Nobuyuki (2009-12-01). "Role of Interleukin-17F in Asthma" (in en). Inflammation & Allergy Drug Targets 8 (5): 383–389. doi:10.2174/1871528110908050383. http://www.eurekaselect.com/openurl/content.php?genre=article&issn=1871-5281&volume=8&issue=5&spage=383. 
  6. ↑ Gorczynski, R. M. (2020), Birbrair, Alexander, ed., "IL-17 Signaling in the Tumor Microenvironment" (in en), Tumor Microenvironment (Cham: Springer International Publishing) 1240: pp. 47–58, doi:10.1007/978-3-030-38315-2_4, ISBN 978-3-030-38314-5, http://link.springer.com/10.1007/978-3-030-38315-2_4, retrieved 2021-06-30 
  7. ↑ 7.0 7.1 Chang, Seon Hee; Dong, Chen (April 2009). "IL-17F: Regulation, signaling and function in inflammation" (in en). Cytokine 46 (1): 7–11. doi:10.1016/j.cyto.2008.12.024. PMID 19233684. PMC 2663007. https://linkinghub.elsevier.com/retrieve/pii/S1043466609000283. 
  8. ↑ Ho, Allen W.; Shen, Fang; Conti, Heather R.; Patel, Nayan; Childs, Erin E.; Peterson, Alanna C.; Hernández-Santos, Nydiaris; Kolls, Jay K. et al. (2010-06-16). "IL-17RC Is Required for Immune Signaling via an Extended SEF/IL-17R Signaling Domain in the Cytoplasmic Tail". The Journal of Immunology 185 (2): 1063–1070. doi:10.4049/jimmunol.0903739. ISSN 0022-1767. PMC 2897912. http://dx.doi.org/10.4049/jimmunol.0903739. 
  9. ↑ Akimzhanov, Askar M.; Yang, Xuexian O; Dong, Chen (March 2007). "Chromatin Remodeling of Interleukin-17 (IL-17)-IL-17F Cytokine Gene Locus during Inflammatory Helper T Cell Differentiation". Journal of Biological Chemistry 282 (9): 5969–5972. doi:10.1074/jbc.c600322200. ISSN 0021-9258. http://dx.doi.org/10.1074/jbc.c600322200. 
  10. ↑ Zhang, Xiaoping; Angkasekwinai, Pornpimon; Dong, Chen; Tang, Hong (January 2011). "Structure and function of interleukin-17 family cytokines" (in en). Protein & Cell 2 (1): 26–40. doi:10.1007/s13238-011-1006-5. ISSN 1674-800X. PMID 21337007. PMC 4875287. http://link.springer.com/10.1007/s13238-011-1006-5. 
  11. ↑ Reis, Joel; Vender, Ron; Torres, Tiago (August 2019). "Bimekizumab: The First Dual Inhibitor of Interleukin (IL)-17A and IL-17F for the Treatment of Psoriatic Disease and Ankylosing Spondylitis" (in en). BioDrugs 33 (4): 391–399. doi:10.1007/s40259-019-00361-6. ISSN 1173-8804. http://link.springer.com/10.1007/s40259-019-00361-6. 
  12. ↑ 12.0 12.1 12.2 Seiderer, Julia; Elben, Ira; Diegelmann, Julia; Glas, Jürgen; Stallhofer, Johannes; Tillack, Cornelia; Pfennig, Simone; Jürgens, Matthias et al. (April 2008). "Role of the novel Th17 cytokine IL-17F in inflammatory bowel disease (IBD): Upregulated colonic IL-17F expression in active Crohnʼs disease and analysis of the IL17F p.His161Arg polymorphism in IBD". Inflammatory Bowel Diseases 14 (4): 437–445. doi:10.1002/ibd.20339. ISSN 1078-0998. http://dx.doi.org/10.1002/ibd.20339. 




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