Enhancement of CCL15 Expression and Monocyte Adhesion to Endothelial Cells (ECs) after Hypoxia/Reoxygenation and Induction of ICAM-1 Expression by CCL15 via the JAK2/STAT3 Pathway in ECs

Abstract

CCL15, a member of the CC chemokine family, is a potent chemoattractant for leukocytes and endothelial cells (ECs). Given that chemokines play key roles in vascular inflammation, we investigated the effects of hypoxia/reoxygenation (H/R) on expression of human CCL15 and a role of CCL15 in upregulating ICAM-1 in ECs. We found that exposure of ECs to H/R increased expression of CCL15 and ICAM-1, which resulted in an increase in monocyte adhesivity to the ECs. Further studies revealed that knockdown of CCL15 or CCR1 attenuated expression of ICAM-1 in ECs after H/R, suggesting that expression of ICAM-1 is upregulated by CCL15. Stimulation of ECs with CCL15 significantly increased expression of ICAM-1 predominantly via the CCR1 receptor. We observed that phosphorylation of JAK2 and STAT3 was stimulated by CCL15 treatment of ECs. Results from reporter and chromatin immunoprecipitation assays revealed that CCL15 activates transcription from the IFN-γ activation site promoter and stimulates binding of STAT3 to the ICAM-1 promoter. Our data also showed that CCL15 increased cell adhesion of human monocytes to ECs under static and shear-stress conditions. Pretreatment of these cells with inhibitors for JAK, PI3K, and AKT prevented the CCL15-induced expression of ICAM-1 and monocyte adhesion to ECs, suggesting the involvement of those signaling molecules in ICAM-1 gene activation by CCL15. The results suggest that CCR1 and its ligands may be a potential target for treating inflammatory diseases involving upregulation of cell adhesion molecules.

Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing

“…3), it was not upregulated after radiation exposure in vivo (Fig. 4), which suggests a role for the tumor microenvironment in ICAM-1 regulation, in agreement with other reports [36]. Further, no significant differences in APM modulation in vivo were observed between fractionated (2 Gy × 5) and single dose (10 Gy × 1) radiation.…”

Propofol ameliorates endothelial inflammation induced by hypoxia/reoxygenation in human umbilical vein endothelial cells: Role of phosphatase A2

“…In the present study, we found 1 h Hypoxia/2 h reoxygenation increased ICAM-1 and E-Selectin protein expression. Our data were consistent with previous studies [21][22][23] which indicated that Hypoxia (range from 1 to 2 h)/reoxygenation (range from 1 to 3 h) could increase endothelial adhesion molecule expression at protein and mRNA level. These findings indicated that 2-3 h H/R was sufficient to induce endothelial adhesion molecule expression.…”

Effect of Carbon Monoxide-Releasing Molecules II-liberated CO on Suppressing Inflammatory Response in Sepsis by Interfering with Nuclear Factor Kappa B Activation

“…ICAM-1 activates leukocytes and endothelial cells (ECs), which in turn prompt the release of various inflammatory mediators, resulting in systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS) and multi-organ dysfunction syndrome (MODS)[48]–[51]. The present results showed that CORM-2 inhibits the increase of ICAM-1 expression in LPS-stimulated HUVECs.…”