ABSTRACT
AMs are well known to mediate interactions between blood cells (leukocyte, platelet) and ECs. Th e coordinated recruitment of leukocytes to sites of infl ammation is largely governed by the time-course and magnitude of endothelial AM expression. Th e expression of AMs during infl ammation is generally transient and quick, but a prolonged and dysregulated AM-mediated process of leukocyte recruitment oft en results in EC dysfunction. It is well established that most of the regulations of infl ammatory AMs in cells are at the transcriptional level. AMs are stimulated when cells are exposed to mediators such as the pro-infl ammatory cytokines, TNF-α and IL-1β. Two transcription factors, NF-kappaB and AP-1, are identifi ed as major regulators responsible for the upregulation of E-selectin, P-selectin, VCAM-1 and ICAM-1 on cytokine-treated ECs. In addition to typical cytokine stimuli, various other AM regulators have been identifi ed (Fig. 1) and most of these regulators are infl uenced by agerelated oxidative stress. For instance, many studies have indicated that oxidized low-density lipoprotein (oxLDL) is an eff ective stimulus for the expression of AMs on ECs. Our recent study reported that the major components of oxLDL, lysophosphatidylcholine (LPC) directly induce the endothelial expression of VCAM-1 and P-selectin through a G-protein coupled receptor 4 pathway (Zou et al. 2007). It was shown that advanced glycation end products (AGEs) enhanced levels of mRNA and antigen for VCAM-1, ICAM-1, and E-selectin in primary cultures of human saphenous vein ECs through engagement of AGE receptor, thereby increasing adhesion of polymorphonuclear leukocytes to stimulated ECs. Age-related oxidative stress is reported to play an important role in the upregulation of infl ammatory AMs. Oxidative stress induced by either depletion of glutathione or generation of reactive species (RS) induced theupregulation of P-selectin and VCAM-1 in ECs. NADPH oxidase-derived RS induce expression of VCAM-1 and ICAM-1 in ECs (Dworakowski et al. 2008). Expressions of both P-selectin and VCAM-1 were induced in a dosedependent manner by XOD/ xanthine, which generates •O2
– and H2O2, indicating the role of reactive oxygen
species in triggering AM expression (Zou et al. 2006).Among several stimuli we tested using the VCAM-1 reporter vector, LPC, TNF-α and IL-1β were highly
eff ective factors inducing VCAM-1 expression (unpublished data). H2O2 promotes adhesion of eosinophils, neutrophils, and monoblastoid U-937 cells via increased expression of integrin CD11β/CD18 molecules (Nagata 2005). Th erefore, the expression of infl ammatory AMs in cells is also regulated by redox status that is signifi cantly changed during the aging process.
