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Abstract #77086 Published in IGR 19-3
Interleukin-6-mediated trans-signaling inhibits transforming growth factor-β signaling in trabecular meshwork cells
Inoue-Mochita M; Inoue T; Kojima S; Futakuchi A; Fujimoto T; Sato-Ohira S; Tsutsumi U; Tanihara HJournal of Biological Chemistry 2018; 293: 10975-10984
Glaucoma is one of the major causes of blindness, and TGF-β2 has been found to be elevated in the aqueous humor of eyes with primary open-angle glaucoma (POAG). TGF-β2 in aqueous humor causes the glaucoma-related fibrosis of human trabecular meshwork (HTM), suggesting an important role of TGF-β in POAG pathogenesis. Here, we sought to elucidate the effects of IL-6 trans-signaling on TGF-β signaling in HTM cells. Using a multiplex immunoassay, POAG patients decreased IL-6 levels and increased soluble IL-6 receptor (sIL-6R) levels compared with the controls. In in vitro experiments, we observed that IL-6 level was increased in the conditioned medium of HTM cells after TGF-β2 stimulation. To elucidate the relationship between TGF-β2 and IL-6 in HTM cells, we conducted Western blotting and immunohistochemical analyses, and we noted that the combination of IL-6 and sIL-6R (IL6/sIL6R) suppressed TGF-β-induced upregulation of α-smooth muscle actin (SMA) in HTM cells, while IL-6 alone did not. This suggests that trans-signaling, not classic signaling, of IL-6 suppresses TGF-β-induced fibrosis of HTM. IL6/sIL6R also suppressed TGF-β-mediated activation of myosin light chain 2 (MLC2), Smad2, and p38. Of note, these inhibitory effects of IL6/sIL6R on TGF-β were partly reduced by siRNA-mediated knockdown of STAT3. Moreover, IL-6/sIL-6R partly inhibited TGF-β-induced activation of the Smad-sensitive promoter detected with luciferase reporter gene assays and upregulation of TGFRI and TGFRII, evaluated by quantitative real-time reverse-transcription PCR. Strikingly, overexpression of TGFRI and TGFRII diminished these inhibitory effects of IL-6/sIL-6R. We conclude that of IL-6-medicated trans-signaling potently represses TGF-β signaling in HTM cells.
Kumamoto University.
Full articleClassification:
2.5.1 Trabecular meshwork (Part of: 2 Anatomical structures in glaucoma > 2.5 Meshwork)
3.6 Cellular biology (Part of: 3 Laboratory methods)
3.9 Pathophysiology (Part of: 3 Laboratory methods)
3.5 Molecular biology incl. SiRNA (Part of: 3 Laboratory methods)
