Extracellular matrix associated protein CCN1 regulates shedding of endothelial ICAM1

Abstract

The extracellular matrix (ECM) provides essential contextual cues for appropriate cellular behavior. CCN1, an ECM associated protein, signals through integrins and heparan sulfate proteoglycans (HSPGs) to mediate multiple cellular responses including proliferation, differentiation, adhesion, migration, and apoptosis. Gene array analysis has identified CCN1 as one of the most highly upregulated genes in a number of TNFα‐mediated inflammatory disorders, including asthma, hyperoxia‐ and ventilator‐induced lung injury, and rheumatoid arthritis. Cytokines such as TNFα upregulate intercellular adhesion molecule 1 (ICAM1) expression in endothelial cells and stimulate shedding of soluble ICAM1. We demonstrate that in endothelial cells in culture, CCN1 inhibits TNFα‐stimulated increases in ICAM1 protein and this inhibition is transcription‐independent. Interestingly, we found that CCN1 promotes shedding of ICAM1 from TNFα‐stimulated endothelial cells via the action of a metalloproteinase. Further, we show that CCN1 acts through αV integrins but not HSPGs to regulate ICAM1 shedding. Together, these findings establish a novel role for CCN1 in regulating ICAM1, and identify CCN1 as a potential therapeutic target in inflammatory disorders. Supported by American Heart Association and NIEHS ES7026.