Blocking IL-6 down-regulates PD-L1 expression and mitigates pulmonary fibrosis by inhibiting the STAT3 signaling pathway

Pulmonary fibrosis is a fatal lung disease. Owing to its unknown pathogenesis, treatment options are limited. Interleukin (IL)-6, a multifunctional cytokine, is overexpressed in pulmonary fibrosis and may contribute to its development through multiple pathways, mainly the signal transduction and transcriptional activator 3 (STAT3) signaling pathway. Moreover, programmed cell death ligand 1 (PD-L1), an immune checkpoint molecule, is crucial in immune regulation and also shows abnormal expression in pulmonary fibrosis, potentially involved in fibrogenesis. PD-L1 may be regulated by IL-6 in pulmonary disorders. Given the pivotal role of IL-6 and PD-L1 in the pathogenesis of pulmonary fibrosis, this study aimed to explore the effect and mechanism of blocking IL-6 on PD-L1 expression and pulmonary fibrosis. We established the pulmonary fibrosis model by instilling bleomycin (BLM) intratracheally into mice and stimulating human fetal lung fibroblasts 1 (HFL1s) with transforming growth factor-beta 1 (TGF-(31). Upon inhibition of IL-6 signaling or reduction of PD-L1 expression, we analyzed the tissue morphology, protein expression and function. We observed elevated expression of IL-6 and PD-L1 in pulmonary fibrosis models. Blocking IL-6 relieved BLM-induced lung tissue destruction, diminished collagen production and deposition and inhibited the expression of alpha smooth muscle actin (alpha-SMA), Vimentin, and Collagen I. Blocking IL-6 could reverse fibroblast-to-myofibroblast transformation induced by TGF-(31 in HFL1s via inhibiting the STAT3 signaling pathway. Interestingly, targeting IL-6/STAT3 signaling could also downregulate PD-L1 expression. Inhibiting PD-L1 could mitigate pulmonary fibrosis. Our findings provide new molecular targets for exploring the pathogenesis and treatment of pulmonary fibrosis.