IL-4 and serum amyloid P inversely regulate fibrocyte differentiation by targeting store-operated Ca2+ channels

Background: Circulating fibrocytes (CFs) have been shown to participate in subepithelial fibrosis of asthma with chronic airflow limitation by acting as an important source of fibroblasts deposited beneath airway epithelia. Serum amyloid P (SAP) is an innate inhibitor of fibrocytes differentiation. Store-operated Ca2+ entry (SOCE) is the major Ca2+ influx of non-excitable cells. In this study, the role of SOCE in the regulation of fibrocytes differentiation and the effects of Th2 cytokine IL-4 and SAP on SOCE of fibrocytes were investigated. Methods: Peripheral blood mononuclear cells or monocytes were cultured in serum-free medium for 7 days to differentiate into fibrocytes; the expression of SOC channels was determined with PCR, SOCE was measured with Ca2+ fluorescence imaging. Results: IL-4 significantly promoted monocyte derived fibrocytes differentiation in vitro. It also increased both SOCE which was induced by thapsigargin or UTP and molecules STIM1 and Orai1 which were related to expression of SOC channels in fibrocytes. Fibrocytes differentiation induced by IL-4 and SOC channels activity could be inhibited by SOC channel blocker SKF-96365. As expected, SAP significantly inhibited IL4-induced differentiation of fibrocytes, the activity of SOCE and the expression of STIM1 and Orai1 in IL-4-treated fibrocytes. Conclusion: IL-4 and SAP reversely regulates cultured fibrocytes differentiation in vitro by respectively promoting or inhibiting the expression and activity of SOC channels in fibrocytes. (c) 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o. o. All rights reserved.