Regulation of endothelial inflammation by TAM receptors

Sammanfattning: The TAM (Tyro3, Axl, Mer) receptors tyrosine kinases together with their ligands Gas6 and protein S play an important role in many cellular processes such as resolution of inflammation and phagocytosis. Notably, they were found to have an important function in vasculature, acting as a pro-survival factors and regulators of angiogenesis. Nevertheless, their role in endothelial inflammation is still poorly understood. Conflicting conclusions have been published, indicating both pro and anti-inflammatory properties of TAM-mediated signaling in endothelium. In this study we sought to elucidate the role of these receptors in endothelial inflammation by measuring the levels of pro-inflammatory markers, such as cytokines and adhesion molecules, in response to inflammatory stimuli in TAM and TAM ligand-deficient human umbilical vein endothelial cells (HUVEC). We found that Axl/Gas6 signaling acts as a pro-inflammatory agent by promoting an increased expression of adhesion molecules and cytokine secretion. Conversely, we suggest anti inflammatory tendencies of the Mer/protein S axis. Moreover, we demonstrate that starvation strongly upregulates Mer expression in HUVEC cells. Finally, we propose that TAM receptors expression is differently regulated depending on cell type, as inflammatory regulators known to induce TAM-expression in immune cells fail to upregulate TAMs in HUVECs. Taken together, we present diversification and complexity of Axl and Mer receptor functions in endothelial inflammation, thus suggesting the need for further investigations.