Certain aspects of membrane damage during hepatitis

This study was to determine the mechanism of tumor necrosis factor-α (TNF-α)-enhanced cyclooxygenase (COX)-2 expression associated with prostaglandin E2 (PGE2) synthesis in human tracheal smooth muscle cells (HTSMCs). TNF-α markedly increased COX-2 expression and PGE2 synthesis in a time- and concentration-dependent manner, whereas COX-1 remained unaltered. Tyrosine kinase inhibitor (genistein), phosphatidylcholine-specific phospholipase C (PC-PLC) inhibitor (D-609) and PKC inhibitor (GF109203X) attenuated TNF-α-induced COX-2 expression and PGE2 synthesis in HTSMCs. TNF-α-induced COX-2 expression and PGE2 synthesis were also inhibited by PD98059 (an inhibitor of MEK1/2) and SB203580 and SB202190 (inhibitors of p38 MAPK), respectively, suggesting the involvement of p42/p44 and p38 MAPKs in these responses. This hypothesis was further supported by that TNF-α induced a transient activation of p42/p44 and p38 MAPKs in a time-and concentration-dependent manner. Furthermore, TNF-α-induced activation of nuclear factor-κB (NF-κB) reversely correlated with the degradation of IκB-α in HTSMCs. TNF-α-induced COX-2 expression and PGE2 synthesis was also inhibited by NF-κB inhibitor pyrrolidinedithiocarbamate (PDTC). These findings suggest that the increased expression of COX-2 correlates with the release of PGE2 from TNF-α-challenged HTSMCs, at least in part, mediated through p42/p44 and p38 MAPKs as well as NF-κB signaling pathways in HTSMCs.