Hostname: page-component-745bb68f8f-g4j75 Total loading time: 0 Render date: 2025-01-09T13:14:47.411Z Has data issue: false hasContentIssue false
  • English
  • Français

IL-17 affects the immune regulation of CD4+ T cells in dilated cardiomyopathy through JAK/STAT pathway

Published online by Cambridge University Press:  06 January 2025

Jie Hao Open the ORCID record for Jie Hao [Opens in a new window] ,
Weiwei Li ,
Wei Jiao ,
Fang Li  and
Yanan Xie
Jie Hao*
Affiliation:
Department of Cardiovascular, The Second Hospital of Hebei Medical University, Shijiazhuang, China
Weiwei Li
Affiliation:
Department of Cardiovascular, The Second Hospital of Hebei Medical University, Shijiazhuang, China
Wei Jiao
Affiliation:
Department of Cardiovascular, The Second Hospital of Hebei Medical University, Shijiazhuang, China
Fang Li
Affiliation:
Department of Cardiovascular, The Second Hospital of Hebei Medical University, Shijiazhuang, China
Yanan Xie
Affiliation:
Department of Cardiovascular, The Second Hospital of Hebei Medical University, Shijiazhuang, China
*
Corresponding author: Jie Hao; Email: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Purpose:

Studying the effect of interleukin-17 (IL-17) on the mechanism of CD4+ T-cell immune regulation and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway may offer new ideas and methods for the therapy of dilated cardiomyopathy.

Methods:

Naive CD4+ T cells were isolated from mice using a magnetic bead sorting reagent and manipulated by overexpression or knockdown of IL-17. Protein levels of Janus kinase 2 (JAK2), phosphorylated JAK2 (p-JAK2), signal transducer and activator of transcription 3 (STAT3), phosphorylated STAT3 (p-STAT3), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9) were determined by Western blotting. Quantitative polymerase chain reaction was used to assess the levels of JAK2, STAT3, MMP-2, and MMP-9. Expression of tumour necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-4 (IL-4), and interferon-gamma (IFNγ) was determined by enzyme-linked immunosorbent assay test kits. TNF-α, IL-1β, IL-4, and IFNγ secretion was measured by flow cytometry.

Results:

In CD4+ T cells, IL-17 overexpression increased TNF-α, IL-1β, IL-4, IFNγ, p-JAK2, p-STAT3, MMP-2, MMP-9 levels, and apoptosis. Knockdown of IL-17 reduced the levels of TNF-α, IL-1β, IL-4, IFNγ, p-JAK2, p-STAT3, MMP-2, and MMP-9, as well as the level of apoptosis.

Conclusion:

Through regulation of IL-17 expression in CD4+ T cells, this study reveals its crucial role in regulating the secretion of inflammatory factors, activation of the JAK/STAT signaling pathway, expression of matrix metalloproteinases, and apoptosis of CD4+ T cells.

Keywords

IL-17JAK/STATCD4+Tdilated cardiomyopathy
Type
Original Article
Information
Cardiology in the Young , First View , pp. 1 - 8
Check for updates
Copyright
© The Author(s), 2025. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Japp, AG, Gulati, A, Cook, SA, Cowie, MR, Prasad, SK. The diagnosis and evaluation of dilated cardiomyopathy. J Am Coll Cardiol 2016; 67: 2996–3010.CrossRefGoogle ScholarPubMed
Reichart, D, Magnussen, C, Zeller, T, Blankenberg, S. Dilated cardiomyopathy: from epidemiologic to genetic phenotypes: a translational review of current literature. J Intern Med 2019; 286: 362–372.CrossRefGoogle ScholarPubMed
Wang, E, Zhou, R, Li, T, et al. The molecular role of immune cells in dilated cardiomyopathy. Medicina (Kaunas) 2023; 59: 1246.CrossRefGoogle ScholarPubMed
Zeng, Z, Wang, K, Li, Y, et al. Down-regulation of microRNA-451a facilitates the activation and proliferation of CD4+ T cells by targeting Myc in patients with dilated cardiomyopathy. J Biol Chem 2017; 292: 6004–6013.CrossRefGoogle ScholarPubMed
Wu, J, Sun, P, Chen, Q, et al. Metabolic reprogramming orchestrates CD4+ T-cell immunological status and restores cardiac dysfunction in autoimmune induced-dilated cardiomyopathy mice. J Mol Cell Cardiol 2019; 135: 134–148.CrossRefGoogle ScholarPubMed
Van der Borght, K, Scott, CL, et al. Myocardial infarction primes autoreactive T cells through activation of dendritic cells. Cell Rep 2017; 18: 3005–3017.CrossRefGoogle ScholarPubMed
Qian, X, Chen, H, Wu, X, Hu, L, Huang, Q, Jin, Y. Interleukin-17 acts as double-edged sword in anti-tumor immunity and tumorigenesis. Cytokine 2017; 89: 34–44.CrossRefGoogle ScholarPubMed
Sundrud, MS, Trivigno, C. Identity crisis of Th17 cells: many forms, many functions, many questions. Semin Immunol 2013; 25: 263–272.CrossRefGoogle ScholarPubMed
Bousoik, E, Montazeri Aliabadi, H. “Do we know Jack” about JAK? A closer look at JAK/STAT signaling pathway. Front Oncol 2018; 8: 287.CrossRefGoogle Scholar
Zhu, J, Paul, WE. Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors. Immunol Rev 2011; 240: 317–262.Google Scholar
Di Napoli, P, Taccardi, AA, Grilli, A, et al. Left ventricular wall stress as a direct correlate of cardiomyocyte apoptosis in patients with severe dilated cardiomyopathy. Am Heart J 2003; 146: 1105–1111.CrossRefGoogle ScholarPubMed
Ibe, W, Saraste, A, Lindemann, S, et al. Cardiomyocyte apoptosis is related to left ventricular dysfunction and remodelling in dilated cardiomyopathy, but is not affected by growth hormone treatment. Eur J Heart Fail 2007; 9: 160–167.CrossRefGoogle Scholar
McKenna, WJ, Maron, BJ, Thiene, G. Epidemiology, and global burden of cardiomyopathies. Circ Res 2017; 121: 722–730.CrossRefGoogle ScholarPubMed
Moeinafshar, A, Yazdanpanah, N, Rezaei, N. Diagnostic biomarkers of dilated cardiomyopathy. Immunobiology 2021; 226: 152153.CrossRefGoogle ScholarPubMed
Crawford, MP, Sinha, S, Renavikar, PS, Borcherding, N, Karandikar, NJ. CD4 T cell-intrinsic role for the T helper 17 signature cytokine IL-17: effector resistance to immune suppression. Proc Natl Acad Sci U S A 2020; 117: 19408–19414.CrossRefGoogle Scholar
Nindl, V, Maier, R, Ratering, D, et al. Cooperation of Th1 and Th17 cells determines transition from autoimmune myocarditis to dilated cardiomyopathy. Eur J Immunol 2012; 42: 2311–2321.CrossRefGoogle ScholarPubMed
Huang, Y, Wu, W, Wang, Y. Expression or secretion of IL-17 in the peripheral blood mononuclear cells from patients with dilated cardiomyopathy. Acta Cardiol 2009; 64: 201–205.CrossRefGoogle ScholarPubMed
Kania, G, Siegert, S, Behnke, S, et al. Innate signaling promotes formation of regulatory nitric oxide-producing dendritic cells limiting T-cell expansion in experimental autoimmune myocarditis. Circulation 2013; 127: 2285–2294.CrossRefGoogle ScholarPubMed
Thome, JJ, Yudanin, N, Ohmura, Y, et al. Spatial map of human T cell compartmentalization and maintenance over decades of life. Cell 2014; 159: 814–828.CrossRefGoogle Scholar
Hu, B, Wang, J, Wu, X, Chen, Y, Yuan, W, Chen, H. Interleukin-17 upregulates vascular endothelial growth factor by activating the JAK/STAT pathway in nucleus pulposus cells. Joint Bone Spine 2017; 84: 327–334.CrossRefGoogle ScholarPubMed
Zhang, M, Xu, M, Wang, K, Li, L, Zhao, J. Effect of inhibition of the JAK2/STAT3 signaling pathway on the Th17/IL-17 axis in acute cellular rejection after heart transplantation in mice. J Cardiovasc Pharmacol 2021; 77: 614–620.CrossRefGoogle ScholarPubMed
Antonov, IB, Kozlov, KL, Pal’tseva, EM, Polyakova, OV, Lin’kova, NS. Matrix metalloproteinases MMP-1 and MMP-9 and their inhibitor TIMP-1 as markers of dilated cardiomyopathy in patients of different age. Bull Exp Biol Med 2018; 164: 550–553.CrossRefGoogle ScholarPubMed
Sperandio, S, de Belle, I, Bredesen, DE. An alternative, nonapoptotic form of programmed cell death. Proc Natl Acad Sci U S A 2000; 97: 14376–14381.CrossRefGoogle ScholarPubMed
Kimura, A, Kishimoto, T. IL-6: Regulator of the Immune System and Key Player in the Pathogenesis of Autoimmune Diseases. In: Kishi, Y (ed). Interleukin-6 in Autoimmunity. Cham, Switzerland: Springer, 2017: 123–142.Google Scholar
Martinez-Moreno, M, Garcia-Castello, A, Ruiz-Llorente, L, et al. The role of IL-17 and the Th17/IL-17 axis in the pathogenesis of autoimmune diseases. Curr Rheumatol Rep 2019; 21: 76.Google Scholar
Wang, Y, Li, Q, Zhang, H, et al. Matrix metalloproteinases in cardiovascular disease: mechanisms and therapeutic implications. J Cardiovasc Pharmacol 2020; 75: 125–137.Google Scholar