IL-6 Regulates The Metabolism And Function Of Human Pulmonary Artery Endothelial Cells Via JAK2/STAT3

Purpose: Pulmonary arterial hypertension(PAH)is one of the complications that leads to poor prognosis in connective tissue disease(CTD)and greatly increases the mortality rate of patients.The primary diseases are systemic sclerosis,systemic lupus erythematosus,and mixed connective tissue disease.Currently,it is believed that the signal transducer and activator of transcription 3(STAT3)pathway plays an important role in the pathogenesis of pulmonary arterial hypertension.This study mainly explores the effect of the inflammatory factor IL-6 on the metabolism and function of pulmonary artery endothelial cells through Janus kinase 2(JAK2)/STAT3 pathway,hoping to reveal some mechanisms of inflammation involved in the onset of CTD-PAH.Method: Human pulmonary artery endothelial cells were selected as the research object,and IL-6 was used to activate JAK2/STAT3 pathway in human pulmonary artery endothelial cells.Western Blot and q PCR were used to detect the activation of JAK2/STAT3 pathway,expression of PFKFB3,HK2,apoptosis-related genes,and growth factors.The lactate content in cell supernatant was detected by lactate assay kit;cell activity was detected by CCK8 technology.Therefore,we studied the regulation of IL-6 on the function and metabolism of human pulmonary artery endothelial cells through JAK2/STAT3 and the intervention of baricitinib and PFKFB3 inhibitor 3PO.Results: IL-6 up-regulated the expression of p-STAT3/STAT3,p-JAK2/JAK2 in human pulmonary artery endothelial cells,expression of glycolysis-related genes PFKFB3 and HK2,apoptosis-related genes caspase-9 and caspase-3,up-regulated transcription levels of growth factors VEGF and PDGF,increased lactate production in cell culture medium;Baricitinib can inhibit glycolysis and apoptosis-related genes,lactate production and up-regulation of growth factors by blocking JAK2/STAT3 pathway;PFKFB3 inhibitor 3PO can reduce VEGF and PDGF transcription up-regulated by IL-6 induction.Conclusion: IL-6 regulates the metabolism and apoptosis-related functions of human pulmonary artery endothelial cells through JAK2/STAT3 pathway,promotes functional disorders of human pulmonary artery endothelial cells,and may play an important role in the initial link of pathogenesis related to connective tissue disease-associated pulmonary arterial hypertension;JAK2/STAT3 pathway and metabolic reprogramming may be potential targets for treatment of connective tissue disease-associated pulmonary arterial hypertension.