Urocortin increased endothelial ICAM1 by cPLA2-dependent NF-κB and PKA pathways in HUVECs

Abstract

Urocortin (Ucn1), a member of the corticotrophin-releasing hormone (CRH) family, has been reported to participate in inflammation. The increased expression of intercellular adhesion molecule 1 (ICAM1) plays important roles in inflammation and immune responses. Our previous results demonstrated that Ucn1 significantly enhanced the expression of ICAM1. However, the underlying mechanisms are still unknown. The purpose of this study is to investigate the detailed mechanisms of Ucn1-induced upregulation of ICAM1. Here, we characterized the mechanisms of Ucn1 usage to regulate ICAM1 expression in human umbilical vein endothelial cells (HUVECs). Our data revealed that Ucn1 increased ICAM1 and cyclooxygenase 2 (COX2) expressions in a time-dependent manner via CRH receptor 2 (CRHR2). In addition, COX2 was involved in ICAM1 upregulation. Furthermore, Ucn1 could increase the expression and phosphorylation of cytosolic phospholipases A2 (cPLA2) in a time-dependent manner via CRHR2 and CRHR1. Moreover, ablation of cPLA2 by the inhibitor pyrrophenone or siRNA attenuated the ICAM1 increase induced by Ucn1. In addition, nuclear factor kB (NF-kB) was activated, indicated by the increase in nuclear p65NF-kB expression and phosphorylation of p65NF-kB, depending on cPLA2 and CRHR2 activation. Pyrrolidinedithiocarbamic acid, an inhibitor of NF-kB, abolished the elevation of ICAM1 but not COX2. Also, Ucn1 increased the production of prostaglandin E 2 (PGE 2 ) which further activated protein kinase A (PKA)-CREB pathways dependent of cPLA2 via CRHR2. Moreover, the increase in NF-kB phosphorylation was not affected by the selective COX2 inhibitor NS-398 or the PKA inhibitor H89. In conclusion, these data indicate that Ucn1 increase the ICAM1 expression via cPLA2-NF-kB and cPLA2-COX2-PGE 2 -PKA-CREB pathways by means of CRHR2.

Visfatin induces the apoptosis of endothelial progenitor cells via the induction of pro-inflammatory mediators through the NF-κB pathway

“…Taken together, the present data suggest that visfatin is an influential upstream factor inducing inflammation and the apoptosis of EPCs, and that its activity results in decreased quantities of EPCs via the upregulation of NF-κB. These findings are in line with those of previous studies demonstrating the involvement of NF-κB in endothelial cell dysfunction and impaired angiogenesis ( 38 , 39 ).…”

Placental CRH as a Signal of Pregnancy Adversity and Impact on Fetal Neurodevelopment

“…Placental CRH exhibits distinct responses to glucocorticoids and during gestation there is a bi-directional release of pCRH into the maternal and fetal compartments ( 29 , 30 ). Acting via type 1 (CRH-R1) and type 2 (CRH-R2) receptors, CRH coordinating homeostatic challenges ( 31 ) that might be crucial in fetal maturation and providing nutritional signals that ultimately control pace of fetal development. It is thus reasonable to assume, that hormonal imbalances associated with severe or prolonged stress response, could potentially affect optimal outcomes ( 18 ).…”

Corticotrophin-releasing factor participates in S1PR3-dependent cPLA2 expression and cell motility in vascular smooth muscle cells

“…Our previous work showed that UCN up-regulated cPLA2 expression via CRFR1 and down-regulated iPLA2 expression via CRFR2 [18]. In HUVECs, UCN time-dependently increased cPLA2 expression and activity via both CRFR1 and CRFR2 [19]. Similarly, both CRF and UCN increased cPLA2 expression in cultured human placental trophoblasts [36].…”

“…urocortin (UCN) was observed to increase cPLA2 expression to promote cell migration by CRFR1, whereas it decreased iPLA2 expression to suppress cell migration by CRFR2 in hepatic cancer cells [18]. In human umbilical vein endothelial cells (HUVECs), UCN increased cPLA2 expression and phosphorylation [19]. Taken together, it is reasonable to speculate a link between CRF system and S1P in the regulation of PLA2.…”