Immunology and Inflammation Research - IL17A

Since IL17A plays an important role in infectious diseases, inflammatory, autoimmune diseases and cancer studies, IL17A has become a hot research target for many studies. In this Gene of the Week article, we have collected some insights on IL17A research progress and development trends, aiming to inspire even more scientific innovations.

Herein, we review the functionality of the IL17A gene and explore its role in immunology and inflammation disease studies.

Background Information – IL17A Gene

IL17A Aliases: Interleukin 17A, Interleukin-17A, IL-17A, IL-17, IL17, Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8), CTLA-8, CTLA8, Cytotoxic T-Lymphocyte-Associated Antigen 8, Cytotoxic T-Lymphocyte-Associated Protein 8

Related Diseases: Arthritis; bronchiolitis obliterans; psoriasis; rheumatoid arthritis (RA); psoriatic arthritis (PsA); multiple sclerosis (MS); and more.

Related Pathways: PEDF Induced Signaling, Immune response IL-23 signaling pathway

Note: the mark ‘√’represents the corresponding models that available from Cyagen AI Knockout Mouse Model eBank.

Overview of IL17A Gene Research

IL-17A (also known as CTLA8, IL17) is a member of the IL-17 receptor family. The protein encoded by IL-17A is a pro-inflammatory cytokine produced by activated T cells. IL-17A mediates downstream pathways involved in the production of inflammatory molecules, chemokines, antimicrobial peptides, and remodeling proteins. The protein encoded by IL-17A is a proinflammatory cytokine that not only plays a key role in inducing innate immune defense, but also has important effects on host defense, cell transport, immune regulation, and tissue repair. This cytokine stimulates non-hematopoietic cells and promotes the production of chemokines, thereby recruiting myeloid cells to the site of inflammation. Additionally, the cytokine protein also regulates the activities of both NF - κB and mitogen-activated protein kinase (MAPK), which can stimulate the expression of IL6 and cyclooxygenase 2 (PTGS2/COX-2) and enhance the production of nitric oxide (NO).

Associated Diseases and Pathologies

IL-17A plays a key role in various infectious diseases, inflammatory and autoimmune disorders, and is a focus of many cancer studies. Several chronic inflammatory diseases are associated with high levels of IL-17A cytokine, including rheumatoid arthritis, psoriasis, and multiple sclerosis (MS). Th17 cells and IL-17 are also related with Crohn's disease (CD) and ulcerative colitis (UC), which are two major forms of inflammatory bowel disease (IBD). The lung injury caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is to a great extent the result of inflammatory response enhanced by cytokines (such as IL17A).

Host Defense and Infection Resistance

In host defense, IL-17A has demonstrated an important role in resisting infections caused by extracellular bacteria and fungi. However, IL-17A seems to be harmful to viral infections, such as influenza, by promoting neutrophil inflammation. In experimental pneumonia models, IL-17A or IL-17RA knockout mice have increased sensitivity to various gram-negative bacteria (such as Klebsiella pneumoniae and Mycoplasma pneumoniae). In contrast, the data suggests that IL-23 and IL-17A do not need to be used to resist primary infection of the Mycobacterium tuberculosis intracellular bacterium. Both IL-17RA knockout mice and IL-23p19 knockout mice cleared the primary infection of Mycobacterium tuberculosis. However, IL-17A is required to protect against primary infections by different intracellular bacteria, known as Francisella.

IL17A Research Models

Thus far, IL-17A studies have been carried out with the following models: IL-17RA knockout mice, IL-17A knockout mice, mouse-adapted influenza virus strain (PR8), and 2009 influenza pandemic H1N1 strain. For these, the results have shown that the presence of IL-17A plays an adverse role in mediating acute lung injury.

Figure 1. Differences of inflammatory cytokines in lung homogenate between wild type mice and IL-17RA knockout mice infected with influenza.

In tumorigenesis, IL-17A can recruit myeloid-derived suppressor cells (MDSC) to weaken anti-tumor immunity. IL-17A can also enhance tumor growth in vivo by inducing IL-6 - which can activate the signal transduction of oncogenic transcription factors and STAT3, and up-regulate tumor survival and angiogenesis genes. IL-17A knockout mice are more sensitive to metastatic pulmonary melanoma, which indicates that IL-17A may promote the production of effective anti-tumor cytokine IFN-γ by cytotoxic T cells. In fact, data from ovarian cancer studies show that Th17 cells are positively correlated with natural killer (NK) cell-mediated immunity and anti-tumor CD8 response.

IL17A Gene Expression in Human and Mouse Tissues

Figure 2. Relative expression levels of IL17A gene mRNA in both human and mouse.

According to the relative expression levels of human and mouse IL17A gene mRNA, the small intestine is the organ with the highest expression, while the expression of duodenum in human and mouse is quite different (the data is normalized within the same species; exact expression level values between mice and human are not to be compared). Data source: NCBI.

IL-17A plays an important role in inflammation, autoimmune diseases, and host defense - having gradually become a hot topic in biomedical and immunological research. IL-17A has ushered in a new era for the treatment of autoimmune diseases. Since the approval of secukinumab, an anti-IL-17A biologic for psoriasis treatment, its sales rose rapidly and have persisted – exemplifying the success of targeting IL-17A in treating autoimmune diseases.

With the growing demand for effective drugs for autoimmune diseases, IL-17 inhibitors are highly anticipated in the fields of inflammation and immunology research. Pharmaceutical companies across the globe continue investing in drug development for autoimmune diseases, with several entering clinical trials or already deployed.

References:

1. Yao Z, Painter SL, Fanslow WC, Ulrich D, Macduff BM, Spriggs MK, Armitage RJ (December 1995). "Human IL-17: a novel cytokine derived from T cells". Journal of Immunology. 155 (12): 5483–6.

2. Kennedy J, Rossi DL, Zurawski SM, Vega F, Kastelein RA, Wagner JL, Hannum CH, Zlotnik A (August 1996). "Mouse IL-17: a cytokine preferentially expressed by alpha beta TCR + CD4-CD8-T cells". Journal of Interferon & Cytokine Research. 16 (8): 611–7.

3. Cua DJ, Tato CM (July 2010). "Innate IL-17-producing cells: the sentinels of the immune system". Nature Reviews. Immunology. 10 (7): 479–89.

4. Mathur AN, Chang HC, Zisoulis DG, Stritesky GL, Yu Q, O'Malley JT, Kapur R, Levy DE, Kansas GS, Kaplan MH (April 2007). "Stat3 and Stat4 direct development of IL-17-secreting Th cells". Journal of Immunology. 178 (8): 4901–7.

5. Yao Z, Fanslow WC, Seldin MF, Rousseau AM, Painter SL, Comeau MR, Cohen JI, Spriggs MK (December 1995). "Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor". Immunity. 3 (6): 811–21.

6. Ye P, Rodriguez FH, Kanaly S, Stocking KL, Schurr J, Schwarzenberger P, Oliver P, Huang W, Zhang P, Zhang J, Shellito JE, Bagby GJ, Nelson S, Charrier K, Peschon JJ, Kolls JK (August 2001). "Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense". The Journal of Experimental Medicine. 194 (4): 519–27.

7. https://en.wikipedia.org/wiki/IL17A

8. https://www.ncbi.nlm.nih.gov/gene/3605

9. https://www.genecards.org/cgi-bin/carddisp.pl?gene=IL17A