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Interleukin-17 in inflammatory skin disorders
What is interleukin-17?
Interleukin (IL)-17 refers to a family of proteins that play critical roles against bacterial infections and fungal infections and in the pathogenesis of autoimmune diseases.
The IL-17 cytokine family consists of six cytokines (interleukins 17A to 17F) and five receptors (interleukins 17RA to 17RE). The interleukins 17A, 17F, and 17A/F heterodimer ligands share a common receptor subunit (interleukin-17RA) for signalling.
IL-17 is mainly produced by a subset of CD4 cells named Th-17 (T–helper 17) cells. It is mainly secreted by activated CD4+ and CD8+ T lymphocytes, while its receptor is found on many cell types.
What is the interleukin-17 pathway?
IL-17 has been classified as a pro-inflammatory cytokine because it induces the expression of mediators of inflammation involved in the proliferation, maturation, and chemotaxis of neutrophils.
- IL-17A and IL-17F are protective against infections on the epithelial surfaces of the skin, lung, and oral cavity [1,2]
- Signalling downstream of IL-17RA/RC elicits the expression of antimicrobial peptides (AMPs), including beta-defensins
- IL-17 acts with IL-22 (produced mainly by T-helper 22 cells in humans) to induce expression of AMPs by keratinocytes [3]
- IL-17A and IL-17F induce cytokines such as:
- Interleukin (IL)-6
- G-CSF (granulocyte colony-stimulating factor)
- GM-CSF (granulocyte-macrophage colony-stimulating factor)
- IL-1β (interleukin 1 beta)
- TGF-β (transforming growth factor-beta)
- TNF-α (tumour necrosis factor-alpha)
- Chemokines, such as IL-8
- Prostaglandins, such as PGE2
- Matrix metalloproteinases (MMP) [3].
Overproduction of interleukins 17A, 17F, and 17A/F is associated with tissue damage and autoimmune diseases such as:
- Rheumatoid arthritis (RA)
- Multiple sclerosis (MS)
- Crohn disease
- Systemic lupus erythematosus (SLE)
- Inflammatory skin diseases such as:
Skin diseases associated with interleukin-17
What is the protective role of interleukin-17 against infections?
The IL-17 family of cytokines play a role in the management of pathogens.
- IL-17F, IL-17A, and IL-17C are important for protection against Staphylococcus aureus (a cause of impetigo) and Candida albicans at epithelial surfaces [5].
- Therapies that block IL-17A and IL-17RA signals have the potential to exacerbate bacterial and fungal infections [6].
The same cytokines have also been reported to have functions outside the skin, at least trials involving mice. IL-17E has a protective role in CNS inflammation and participates in protective responses against parasites in the intestine [7–9].
Infections protected by IL-17
What skin diseases involve interleukin-17?
Skin diseases in which interleukin-17 is involved or is thought to be involved are as follows.
Psoriasis
Psoriasis is a chronic inflammatory skin condition characterised by epidermal hyperplasia.
- Elevated IL-17A and Th17-related cytokines, such as IL-22 and IL-23, are found in psoriatic plaques.
- The IL-17A-blocking monoclonal antibodies secukinumab and ixekizumab and the IL-17RA-targeting antibody brodalumab result in marked improvement and sometimes complete clearance of psoriasis [10–12].
- Several other molecules targeting the IL-17 family are in clinical development (eg, bimekizumab, which targets IL-17A and IL-17F), as are drugs targeting IL-23, which is upstream of IL-17, and signalling molecules, which are downstream [13,14].
Psoriasis
Dermatitis
The role of IL-17 is under investigation in various forms of dermatitis.
- Serum levels of IL-17A and F are increased in children with atopic dermatitis and are correlated with disease severity.
- Expression of IL-17A at the mRNA level is increased in the skin of patients with allergic contact dermatitis due to nickel allergy [15].
Skin cancer
IL-17 signalling has been associated with the development of skin cancer during chemical carcinogenesis in mouse models.
- This pro-tumourigenic effect of IL-17 is thought to occur via the promotion of epithelial proliferation and the anti-apoptotic effect of the transcription factor STAT-3 (Signal Transducer and Activator of Transcription 3), which may be downstream of IL-17-induced genes such as IL-6.
- IL-17A blockade may prove useful for controlling at least some cancers [16]. This is unproven in humans
Epithelial skin cancers
What are the future indications of the study of interleukin-17?
The proinflammatory properties of IL-17 are protective against infection. A good understanding of the different roles played by the IL-17 cytokines is necessary to design effective drugs relating to pathogenesis and mechanisms of inflammation.
- Unrestrained IL-17 signalling is associated with immunopathology, autoimmune disease, and cancer progression.
- IL-17 inhibitors are proving valuable in the control of inflammatory skin disease.
- Analysis of the roles of individual components of the IL-17 pathway in infection and inflammation is ongoing.
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References
- Ye P, Garvey PB, Zhang P, et al. Interleukin-17 and lung host defense against Klebsiella pneumoniae infection. Am J Respir Cell Mol Biol. 2001;25(3):335-40. doi:10.1165/ajrcmb.25.3.4424. PubMed
- Dubin PJ, Martz A, Eisenstatt JR, Fox MD, Logar A, Kolls JK. Interleukin-23-mediated inflammation in Pseudomonas aeruginosa pulmonary infection. Infect Immun. 2012;80(1):398-409. doi:10.1128/IAI.05821-11. PubMed
- Shen F, Gaffen SL. Structure-function relationships in the IL-17 receptor: implications for signal transduction and therapy. Cytokine. 2008;41(2):92-104. doi:10.1016/j.cyto.2007.11.013. PubMed Central
- Monin L, Gaffen SL. Interleukin 17 family cytokines: signaling mechanisms, biological activities, and therapeutic implications. Cold Spring Harb Perspect Biol. 2018;10(4):a028522. doi:10.1101/cshperspect.a028522. PubMed
- Reynolds JM, Martinez GJ, Nallaparaju KC, Chang SH, Wang YH, Dong C. Cutting edge: regulation of intestinal inflammation and barrier function by IL-17C. J Immunol. 2012;189(9):4226-30. doi:10.4049/jimmunol.1103014. PubMed
- Ishigame H, Kakuta S, Nagai T, et al. Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity. 2009;30(1):108-19. doi:10.1016/j.immuni.2008.11.009. PubMed
- Kleinschek MA, Owyang AM, Joyce-Shaikh B, et al. IL-25 regulates Th17 function in autoimmune inflammation. J Exp Med. 2007;204(1):161-70. doi:10.1084/jem.20061738. PubMed
- Angkasekwinai P, Srimanote P, Wang YH, et al. Interleukin-25 (IL-25) promotes efficient protective immunity against Trichinella spiralis infection by enhancing the antigen-specific IL-9 response. Infect Immun. 2013;81(10):3731-41. doi:10.1128/IAI.00646-13. PubMed
- Owyang AM, Zaph C, Wilson EH, et al. Interleukin 25 regulates type 2 cytokine-dependent immunity and limits chronic inflammation in the gastrointestinal tract. J Exp Med. 2006;203(4):843-9. doi:10.1084/jem.20051496. PubMed
- Kikly K, Liu L, Na S, Sedgwick JD. The IL-23/Th(17) axis: therapeutic targets for autoimmune inflammation [published correction appears in Curr Opin Immunol. 2007 Feb;19(1):111]. Curr Opin Immunol. 2006;18(6):670-5. doi:10.1016/j.coi.2006.09.008. PubMed
- Griffiths CE, Reich K, Lebwohl M, et al. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet. 2015;386(9993):541-51. doi:10.1016/S0140-6736(15)60125-8. PubMed
- Papp KA, Langley RG, Sigurgeirsson B, et al. Efficacy and safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled phase II dose-ranging study. Br J Dermatol. 2013;168(2):412-21. doi:10.1111/bjd.12110. PubMed
- Conrad C, Gilliet M. Psoriasis: from pathogenesis to targeted therapies. Clin Rev Allergy Immunol. 2018;54(1):102-13. doi:10.1007/s12016-018-8668-1. PubMed
- Glatt S, Baeten D, Baker T, et al. Dual IL-17A and IL-17F neutralisation by bimekizumab in psoriatic arthritis: evidence from preclinical experiments and a randomised placebo-controlled clinical trial that IL-17F contributes to human chronic tissue inflammation. Ann Rheum Dis. 2018;77(4):523-32. doi:10.1136/annrheumdis-2017-212127. PubMed
- He D, Wu L, Kim HK, Li H, Elmets CA, Xu H. CD8+ IL-17-producing T cells are important in effector functions for the elicitation of contact hypersensitivity responses. J Immunol. 2006;177(10):6852-8. doi:10.4049/jimmunol.177.10.6852. PubMed
- Wang L, Yi T, Zhang W, Pardoll DM, Yu H. IL-17 enhances tumor development in carcinogen-induced skin cancer. Cancer Res. 2010;70(24):10112-10120. doi:10.1158/0008-5472.CAN-10-0775. PubMed