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Gastrointestinal Biology

IL-17A and IL-17F are key cytokines involved in signaling pathways that regulate cytokine production in intestinal epithelial cells and signaling in gastric cells. IL-17A, more potent than IL-17F, interacts with TNF-α to modulate gene expression, influencing diseases like IBD and gastric cancer by activating pathways like EGFR, ERK and NF-κB.

FAQs About IL-17 and Gastrointestinal Biology

What roles do IL-17A and IL-17F play in gastrointestinal biology?

IL-17A and IL-17F contribute protective roles in a healthy functioning gastrointestinal system and can promote the pathogenesis of many diseases, including inflammatory bowel disease, when dysregulated. These cytokines are produced by T-helper 17 (Th17) cells, γδT cells, type 3 innate lymphoid cells (ILC3s), natural killer (NK) cells, NKT cells, neutrophils, mucosal-associated invariant T cells, Paneth cells and mast cells (1, 2).

The intestinal epithelium acts as a barrier against pathogens and, when compromised, can lead to inflammatory bowel diseases. IL-17, which includes IL-17A and IL-17F, plays a crucial role in maintaining the integrity of the intestinal epithelium and mucosal barrier and preventing pathogen invasion (1, 3). These cytokines act on intestinal epithelial cells through the IL-17 receptor, IL-17RA and IL-17RC (4). These receptors engage with the cytoplasmic protein ACT1. ACT1 then recruits and ubiquitinates TNF-receptor associated factor 6 (TRAF6), leading to the activation of downstream signaling pathways, including protein kinase (MAPK), CCAAT-enhancer-binding protein β (C/EBPβ) and nuclear factor κB (NF-κB) pathways. This triggers transcriptional activation of downstream target genes that stimulate antimicrobial peptide production and adaptive immune cell recruitment. They also help maintain barrier integrity by promoting epithelial regeneration following inflammation (5).

How do IL-17A and IL-17F differentially regulate cytokine production in intestinal epithelial cells?

IL-17A and IL-17F are 50% identical and have many similar biological properties. For instance, both promote cytokine production in intestinal epithelial cells (6). However, IL-17A can induce a stronger transcriptional response, particularly in upregulating pro-inflammatory genes, because it has a stronger affinity for the IL-17RA/RC complex (7). IL-17F, on the other hand, has less potent effects in regulating cytokine production, possibly due to having at least a 100-fold lower affinity for the IL-17RA/RC complex than IL-17A (5, 8).

In addition, both IL-17A and IL-17F regulate the production of chemokines such as CXCL1, CCL5, CCL2, GM-CSF and IFN-γ. IL-17A alone regulates TNF-α, IL-12, IL-3 and IL-1α expression.

What is the significance of IL-17A signaling in gastric cells?

IL-17A signaling in gastric cells plays a crucial role in contributing to the protective functions of a healthy gastrointestinal system and in the pathogenesis of various gastric diseases. IL-17A signals by binding to receptors IL-17RA and IL-17RC, triggering the activation of intracellular signaling pathways like NF-κB to perform a wide range of functions. These functions include regulating the gut microbiota, controlling the proliferation and apoptosis of gastric epithelial cells, promoting inflammation, immune cell recruitment, inducing antimicrobial host defense in the gastric mucosa against diseases like Helicobacter pylori infection, and removal of other pathogens like Mycoplasma pneumonia, Candida albicans, Klebsiella pneumoniae, Blastomyces dermatitidis and Histoplasma capsulatum (9, 10, 11). However, dysregulated IL-17A signaling has been associated with the development of gastric cancer and other gastritis-related conditions, making it a therapeutic target for these diseases.

Why is understanding the regulation of IL-17A and IL-17F crucial for medical treatments in gastrointestinal diseases?

Understanding the regulation of IL-17A and IL-17F helps in the development of targeted treatments for inflammatory gastrointestinal diseases like Crohn's disease and ulcerative colitis based on cytokine profiles and signaling pathway activation. Drugs that target these cytokines or their receptors could reduce excessive inflammation while keeping the immune system working properly. For example, biological therapies targeting the IL-17 pathway, including secukinumab, bimekizumab and ixekizumab, have shown efficacy in psoriasis and are under research for their potential in addressing inflammatory bowel disease by modulating disease-specific inflammatory pathways (12, 13). Uncovering the molecular-level regulation of these cytokines also helps to identify biomarkers for disease activity and therapy response.

How does IL-17A interact with other cytokines and cells in the gastrointestinal environment?

The role of IL-17A in the gastrointestinal environment is mediated through the interaction with other cytokines and cells. For example, its inflammatory effect in the intestinal mucosa is primarily linked to its activation and recruitment of immune cells and its synergistic effects with other proinflammatory cytokines, including TNF, IL-1β, IFNγ, GM-CSF and IL-22 (14). In addition, the inflammatory response of IL-17 activity is typically regulated by T cells and anti-inflammatory cytokines such as IL-10, TGFβ and IL-35. Dysregulated IL-17 responses can contribute to pathologies like infection and autoimmunity (2).

What are the health consequences of overactive IL-17A and IL-17F signaling in the gastrointestinal tract?

Overactive IL-17A and IL-17F signaling can lead to chronic inflammation and tissue damage associated with gastrointestinal inflammatory and autoimmune diseases, including inflammatory bowel diseases (15). IL-17 levels have been shown to be significantly elevated in patients with active ulcerative colitis and Crohn’s disease. Excessive production of these cytokines can contribute to pathological events associated with these conditions, including the disruption of intestinal barrier function.

Elevated IL-17A expression is also implicated in gastric cancer progression and metastasis, promoting tumor cell migration and invasion, chemotherapy resistance and immunosuppression. However, the specific role of IL-17A in cancer development and progression is not fully understood. Some studies have shown that IL-17A increases gastric cancer cell migration and invasion by activating the NF-kB pathway and subsequently increasing MMP-2 and MMP-9 levels (9).

How does the underactivity of IL-17A and IL-17F impact gastrointestinal health?

Reduced IL-17A and IL-17F activity through biologic inhibitors, for example, can compromise the integrity of the intestinal barrier and disrupt the bacterial and fungal coexistence in the gut microbiome, increasing susceptibility to infections and inflammatory bowel diseases (17). Studies have found that IL-17 inhibitor therapy is associated with exacerbation or new-onset of IBD and colitis (13).

References and further reading

  1. Sun L, Wang L, Moore BB, et al. IL-17: Balancing Protective Immunity and Pathogenesis. J Immunol Res. 2023;2023:3360310. Published 2023 Aug 12.
  2. Mills KHG. IL-17 and IL-17-producing cells in protection versus pathology. Nat Rev Immunol. 2023;23(1):38-54.
  3. Valeri M, Raffatellu M. Cytokines IL-17 and IL-22 in the host response to infection. Pathog Dis. 2016;74(9):ftw111.
  4. Monin L, Gaffen SL. Interleukin 17 Family Cytokines: Signaling Mechanisms, Biological Activities, and Therapeutic Implications. Cold Spring Harb Perspect Biol. 2018;10(4):a028522. Published 2018 Apr 2.
  5. Iznardo H, Puig L. Dual inhibition of IL-17A and IL-17F in psoriatic disease. Ther Adv Chronic Dis. 2021;12:20406223211037846. Published 2021 Aug 12.
  6. Pappu R, Ramirez-Carrozzi V, Sambandam A. The interleukin-17 cytokine family: critical players in host defence and inflammatory diseases. Immunology. 2011;134(1):8-16.
  7. Adams R, Maroof A, Baker T, et al. Bimekizumab, a Novel Humanized IgG1 Antibody That Neutralizes Both IL-17A and IL-17F. Front Immunol. 2020;11:1894. Published 2020 Aug 21.
  8. Sánchez-Rodríguez G, Puig L. Pathogenic Role of IL-17 and Therapeutic Targeting of IL-17F in Psoriatic Arthritis and Spondyloarthropathies. Int J Mol Sci. 2023;24(12):10305. Published 2023 Jun 18.
  9. Kang JH, Park S, Rho J, et al. IL-17A promotes Helicobacter pylori-induced gastric carcinogenesis via interactions with IL-17RC. Gastric Cancer. 2023;26(1):82-94.
  10. Dixon BR, Radin JN, Piazuelo MB, Contreras DC, Algood HM. IL-17a and IL-22 Induce Expression of Antimicrobials in Gastrointestinal Epithelial Cells and May Contribute to Epithelial Cell Defense against Helicobacter pylori. PLoS One. 2016;11(2):e0148514. Published 2016 Feb 11.
  11. Rex DAB, Dagamajalu S, Gouda MM, et al. A comprehensive network map of IL-17A signaling pathway. J Cell Commun Signal. 2023;17(1):209-215.
  12. Liu T, Li S, Ying S, et al. The IL-23/IL-17 Pathway in Inflammatory Skin Diseases: From Bench to Bedside. Front Immunol. 2020;11:594735. Published 2020 Nov 17.
  13. Deng Z, Wang S, Wu C, Wang C. IL-17 inhibitor-associated inflammatory bowel disease: A study based on literature and database analysis. Front Pharmacol. 2023;14:1124628. Published 2023 Mar 23.
  14. Ruiz de Morales JMG, Puig L, Daudén E, et al. Critical role of interleukin (IL)-17 in inflammatory and immune disorders: An updated review of the evidence focusing in controversies. Autoimmun Rev. 2020;19(1):102429.
  15. Grümme L, Dombret S, Knösel T, Skapenko A, Schulze-Koops H. Colitis induced by IL-17A-inhibitors. Clin J Gastroenterol. 2024;17(2):263-270.
  16. Fakharian F, Thirugnanam S, Welsh DA, et al. The Role of Gut Dysbiosis in the Loss of Intestinal Immune Cell Functions and Viral Pathogenesis. Microorganisms. 2023;11(7):1849. Published 2023 Jul 21.
  17. Manasson J, Wallach DS, Guggino G, et al. Interleukin-17 Inhibition in Spondyloarthritis Is Associated With Subclinical Gut Microbiome Perturbations and a Distinctive Interleukin-25-Driven Intestinal Inflammation. Arthritis Rheumatol. 2020;72(4):645-657. 

 

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