Interleukin‐2 induces extracellular matrix synthesis and TGF‐β2 expression in retinal pigment epithelial cells

Abstract

Macular fibrosis is a vital obstacle of vision acuity improvement of age‐related macular degeneration patients. This study was to investigate the effects of interleukin 2 (IL‐2) on epithelial‐mesenchymal transition (EMT), extracellular matrix (ECM) synthesis and transforming growth factor β2 (TGF‐β2) expression in retinal pigment epithelial (RPE) cells. 10 μg/L IL‐2 was used to induce fibrosis in RPE cells for various times. Western blot was used to detect the EMT marker α‐smooth muscle actin (α‐SMA), ECM markers fibronectin (Fn) and type 1 collagen (COL‐1), TGF‐β2, and the activation of the JAK/STAT3 and NF‐κB signaling pathway. Furthermore, JAK/STAT3 and NF‐κB signaling pathways were specifically blocked by WP1066 or BAY11‐7082, respectively, and the expression of α‐SMA, COL‐1, Fn and TGF‐β2 protein were detected. Wound healing and Transwell assays were used to measure cell migration ability of IL‐2 with or without WP1066 or BAY11‐7082. After induction of IL‐2, the expressions of Fn, COL‐1, TGF‐β2 protein were significantly increased, and this effect was correlated with IL‐2 treatment duration, while α‐SMA protein expression did not change significantly. Both WP1066 and BAY11‐7082 could effectively downregulate the expression of Fn, COL‐1 and TGF‐β2 induced by IL‐2. What's more, both NF‐κB and JAK/STAT3 inhibitors could suppress the activation of the other signaling pathway. Additionally, JAK/STAT3 inhibitor WP1066 and NF‐κB inhibitor BAY 11‐7082 could obviously decrease RPE cells migration capability induced by IL‐2. IL‐2 promotes cell migration, ECM synthesis and TGF‐β2 expression in RPE cells via JAK/STAT3 and NF‐κB signaling pathways, which may play an important role in proliferative vitreoretinopathy.

The Role of Inflammation in Age-Related Macular Degeneration

“…IL-1 receptor antagonist (IL-1Ra) treatment that inhibits IL-1β significantly suppressed CNV 56 - 58 . IL-2 participates in RPE cell migration, extracellular matrix (ECM) synthesis, TGF-β2 expression, indicating that IL-2 makes a constructive effect on the fibrosis of macular degeneration 59 . IL-6 is a key mediator for promoting subretinal fibrosis, which is considered as an injured repair in damaged organs 60 , and serum IL-6 level correlates with GA 61 .…”

The HIF‐1α/p53/miRNA‐34a/Klotho axis in retinal pigment epithelial cells promotes subretinal fibrosis and exacerbates choroidal neovascularization

“…In the context of AMD, RPE cells lose their cell‐cell adhesions and apical‐basal polarity, transforming into mesenchymal cells via EMT 3 . Multiple extracellular ligands, such as galectin‐1 4 and interleukin‐2 (IL‐2), 5 are involved in the initiation and development of the EMT programme in RPE cells 6 . Thoroughly studied for its central role in control of EMT, the ligand transforming growth factor‐beta (TGF‐β) is identified as the master regulator of EMT process 7,8 .…”

Triamcinolone acetonide modulates TGF‑β2‑induced angiogenic and tissue‑remodeling effects in cultured human retinal pigment epithelial cells

“…TGF-β2 is considered a key component in the development of abnormal fibrosis in the pathological environment. Various studies have confirmed TGF-β2 as a dominant factor in the development of age-related macular degeneration and macular fibrosis or atrophy ( 49 , 50 ). The present results demonstrated that TA not only enhanced cell viability in TGF-β2-treated RPE cells, but also suppressed contractility in collagen gels.…”