Receptor And Intracellular Signaling Mechanisms Involved In TNFα-induced Expression Of Heme Oxygenase-1 In Murine Brain Microvessel Endothelial Cells

Heme oxygenase-1 (HO-1) is a stress protein and the rate-limiting enzyme in heme degradation. It is suggested that upon induction, HO-1 may play a protective role in the cardiovascular system by producing carbon monoxide - a gaseous cellular messager that functions as the nitric oxide in many aspects, and the antioxidants, bilirubin and biliverdin. Tumor necrosis factor a (TNFa), a pleiotropic cytokine that participates in the inflammatory and immune responses, has recently been shown to be able to induce the HO-1 expression in vascular endothelial cells (ECs). However, the underlying mechanisms remain to be elucidated. Our previous result showed that the induction of HO-1 by TNFa also occurred in the ECs with the type1TNF receptor (TNFR1) knockout, suggesting a role for type II receptor (TNFR2) in mediating the TNFa-induced HO-1 expression. In this study, we explored the TNFR2-related intracellular signaling mechanisms that are responsible for induction of HO-1 in the TNFR1 knockout murine brain microvessel endothelial cells [BVEC/TNFRI(-/-)]. The following aspects were studied in the BVEC/TNF-RI(-/-):1. Role of ROS in the TNFa-induced expression of HO-1.2. Role of ERK and JNK in the TNFa-induced expression of HO-1.3. The transcription factors involved in the expression of HO-1 induced by TNFa.