Interleukin 35 Regulates Interleukin 17 Expression and T Helper 17 in Patients with Proliferative Diabetic Retinopathy

Overview

Journal Bioengineered

Date 2022 May 31

PMID 35635032

Authors

Ai Yan

Ying Zhang

Xiaocong Wang

Yueling Cui

Wei Tan

Affiliations

Soon will be listed here.

Abstract

T helper 17 (Th17) cells regulate inflammatory processes and are implicated in pathogenesis of proliferative diabetic retinopathy (PDR) through modulation of interleukin-17 (IL-17). IL-35, anti-inflammatory factor, negatively mediates IL-17 expression and Th17 differentiation. In this study, the role of IL-35 in PDR was assessed. The results showed that IL-35 was down-regulated, while IL-17 was up-regulated, in peripheral blood mononuclear cells (PBMCs) of PDR patients. In addition, immunofluorescence analysis indicated that frequency of Th17 cells was enhanced in the PBMCs of PDR patients. However, incubation with IL-35 reduced the Th17 cell frequency and decreased the level of IL-17 in CD4 T lymphocytes. Moreover, the levels of transcription factors essential for Th17 differentiation, ROR α (retinoid-related orphan receptor alpha) and ROR γt, were reduced by IL-35 treatment. In conclusion, IL-35 reduced level of IL-17 and inhibited Th17 differentiation to protect against PDR.

Citing Articles

Emerging role of adaptive immunity in diabetes-induced cognitive impairment: from the periphery to the brain.

Yang G, Su R, Bu J, Li Y, Lin X, Jin J Metab Brain Dis. 2025; 40(1):102.

PMID: 39821703 DOI: 10.1007/s11011-025-01532-x.

Ocular immune-related diseases: molecular mechanisms and therapy.

Wang Y, Gao S, Cao F, Yang H, Lei F, Hou S MedComm (2020). 2024; 5(12):e70021.

PMID: 39611043 PMC: 11604294. DOI: 10.1002/mco2.70021.

Interleukin-35: A key player managing pre-diabetes and chronic inflammatory type 1 autoimmune diabetes.

Chakraborty R, Mukherjee A, Bala A World J Diabetes. 2024; 15(10):2147-2151.

PMID: 39493554 PMC: 11525726. DOI: 10.4239/wjd.v15.i10.2147.

The IL-12 family of cytokines: pathogenetic role in diabetic retinopathy and therapeutic approaches to correction.

Wang D, Liu R Naunyn Schmiedebergs Arch Pharmacol. 2024; 398(1):125-133.

PMID: 39120722 DOI: 10.1007/s00210-024-03360-9.

Cell and molecular targeted therapies for diabetic retinopathy.

Reddy S, Devi V, Seetharaman A, Shailaja S, Bhat K, Gangaraju R Front Endocrinol (Lausanne). 2024; 15:1416668.

PMID: 38948520 PMC: 11211264. DOI: 10.3389/fendo.2024.1416668.

References

Yu H, Liu B, Wu G, Du Z, Wu Q, Zeng X . Dysregulation of circulating follicular helper T cells in type 2 diabetic patients with diabetic retinopathy. Immunol Res. 2021; 69(2):153-161. DOI: 10.1007/s12026-021-09182-8. View

Takeuchi M, Sato T, Tanaka A, Muraoka T, Taguchi M, Sakurai Y . Elevated Levels of Cytokines Associated with Th2 and Th17 Cells in Vitreous Fluid of Proliferative Diabetic Retinopathy Patients. PLoS One. 2015; 10(9):e0137358. PMC: 4564282. DOI: 10.1371/journal.pone.0137358. View

Okada K, Fujimura T, Kikuchi T, Aino M, Kamiya Y, Izawa A . Effect of interleukin (IL)-35 on IL-17 expression and production by human CD4 T cells. PeerJ. 2017; 5:e2999. PMC: 5314955. DOI: 10.7717/peerj.2999. View

Zapadka T, Lindstrom S, Batoki J, Lee C, Taylor B, Howell S . Aryl Hydrocarbon Receptor Agonist VAF347 Impedes Retinal Pathogenesis in Diabetic Mice. Int J Mol Sci. 2021; 22(9). PMC: 8122442. DOI: 10.3390/ijms22094335. View

Chernykh V, Varvarinsky E, Smirnov E, Chernykh D, Trunov A . Proliferative and inflammatory factors in the vitreous of patients with proliferative diabetic retinopathy. Indian J Ophthalmol. 2015; 63(1):33-6. PMC: 4363955. DOI: 10.4103/0301-4738.151464. View

Kroll P, Rodrigues E, Hoerle S . Pathogenesis and classification of proliferative diabetic vitreoretinopathy. Ophthalmologica. 2007; 221(2):78-94. DOI: 10.1159/000098253. View

Chen H, Ren X, Liao N, Wen F . Th17 cell frequency and IL-17A concentrations in peripheral blood mononuclear cells and vitreous fluid from patients with diabetic retinopathy. J Int Med Res. 2016; 44(6):1403-1413. PMC: 5536736. DOI: 10.1177/0300060516672369. View

Wang Y, Mao Y, Zhang J, Shi G, Cheng L, Lin Y . IL-35 recombinant protein reverses inflammatory bowel disease and psoriasis through regulation of inflammatory cytokines and immune cells. J Cell Mol Med. 2017; 22(2):1014-1025. PMC: 5783847. DOI: 10.1111/jcmm.13428. View

Gunduz K, Bakri S . Management of proliferative diabetic retinopathy. Compr Ophthalmol Update. 2008; 8(5):245-56. View

10.

Takeuchi M, Sato T, Sakurai Y, Taguchi M, Harimoto K, Karasawa Y . Association between aqueous humor and vitreous fluid levels of Th17 cell-related cytokines in patients with proliferative diabetic retinopathy. PLoS One. 2017; 12(5):e0178230. PMC: 5448770. DOI: 10.1371/journal.pone.0178230. View

11.

Rubsam A, Parikh S, Fort P . Role of Inflammation in Diabetic Retinopathy. Int J Mol Sci. 2018; 19(4). PMC: 5979417. DOI: 10.3390/ijms19040942. View

12.

Feng S, Yu H, Yu Y, Geng Y, Li D, Yang C . Levels of Inflammatory Cytokines IL-1, IL-6, IL-8, IL-17A, and TNF- in Aqueous Humour of Patients with Diabetic Retinopathy. J Diabetes Res. 2018; 2018:8546423. PMC: 5904804. DOI: 10.1155/2018/8546423. View

13.

Li Y, Wang Y, Liu H, Ding K, Hao S, Shao Y . Lower level of IL‑35 and its reduced inhibition in Th17 cells in patients with bone marrow mononuclear cells Coombs test‑positive hemocytopenia. Mol Med Rep. 2017; 17(2):2973-2981. PMC: 5783516. DOI: 10.3892/mmr.2017.8252. View

14.

Liu S, Li Y, Xia L, Shen H, Lu J . IL-35 prevent bone loss through promotion of bone formation and angiogenesis in rheumatoid arthritis. Clin Exp Rheumatol. 2019; 37(5):820-825. View

15.

Kuwabara T, Ishikawa F, Kondo M, Kakiuchi T . The Role of IL-17 and Related Cytokines in Inflammatory Autoimmune Diseases. Mediators Inflamm. 2017; 2017:3908061. PMC: 5337858. DOI: 10.1155/2017/3908061. View

16.

Li X, Fang P, Yang W, Wang H, Yang X . IL-35, as a newly proposed homeostasis-associated molecular pattern, plays three major functions including anti-inflammatory initiator, effector, and blocker in cardiovascular diseases. Cytokine. 2017; 122:154076. PMC: 5741534. DOI: 10.1016/j.cyto.2017.06.003. View

17.

Jagannathan-Bogdan M, McDonnell M, Shin H, Rehman Q, Hasturk H, Apovian C . Elevated proinflammatory cytokine production by a skewed T cell compartment requires monocytes and promotes inflammation in type 2 diabetes. J Immunol. 2010; 186(2):1162-72. PMC: 3089774. DOI: 10.4049/jimmunol.1002615. View

18.

Qu N, Xu M, Mizoguchi I, Furusawa J, Kaneko K, Watanabe K . Pivotal roles of T-helper 17-related cytokines, IL-17, IL-22, and IL-23, in inflammatory diseases. Clin Dev Immunol. 2013; 2013:968549. PMC: 3728507. DOI: 10.1155/2013/968549. View

19.

Yang X, Pappu B, Nurieva R, Akimzhanov A, Kang H, Chung Y . T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity. 2008; 28(1):29-39. PMC: 2587175. DOI: 10.1016/j.immuni.2007.11.016. View

20.

Jiang Y, Wang J, Li H, Xia L . IL-35 alleviates inflammation progression in a rat model of diabetic neuropathic pain via inhibition of JNK signaling. J Inflamm (Lond). 2019; 16:19. PMC: 6651949. DOI: 10.1186/s12950-019-0217-z. View