Crosstalk between the JAK2 and TGF-β1 signaling pathways in scleroderma-related interstitial lung disease targeted by baricitinib.

BACKGROUND AND

objectiveSystemic sclerosis (SSc) is an immune-mediated rheumatic disease characterized by fibrosis and vascular lesions. Interstitial lung disease is an early complication of SSc and the main cause of death from SSc. Although baricitinib shows good efficacy in a variety of connective tissue diseases, its role in systemic sclerosis-related interstitial lung disease (SSc-ILD) is unclear. The objective of our study was to explore the effect and mechanism of baricitinib in SSc-ILD.

methodsWe explored crosstalk between the JAK2 and TGF-β1 pathways. In vivo experiments, SSc-ILD mice model were constructed by subcutaneous injection of PBS or bleomycin (7.5 mg/kg) and intragastric administration of 0.5% CMC-Na or baricitinib (5 mg/kg) once every two days. We used ELISA, qRT‒PCR, western blot and immunofluorescence staining to evaluate the degree of fibrosis. In vitro experiments, we used TGF-β1 and baricitinib to stimulate human fetal lung fibroblasts (HFLs) and assessed protein expression by western blot.

resultsThe vivo experiments showed that baricitinib notably alleviated skin and lung fibrosis, decreased the concentration of pro-inflammatory factors and increased those of the anti-inflammatory factors. Baricitinib affected the expression of TGF-β1 and TβRI/II inhibitiing JAK2. In the vitro experiments, following the culture of HFLs with baricitinib or a STAT3 inhibitor for 48 h, the expression levels of TβRI/II decreased. Conversely, with successful inhibition of TGF-β receptors in HFLs, JAK2 protein expression decreased.

conclusionsBaricitinib attenuated bleomycin-induced skin and lung fibrosis in SSc-ILD mice model by targeting JAK2 and regulating of the crosstalk between the JAK2 and TGF-β1 signaling pathways.