p38 mitogen-activated protein kinase and c-Jun-NH2-terminal kinase regulate RANTES production by influenza virus-infected human bronchial epithelial cells

Airway epithelial cells which are the initial site of influenza virus (IV) infection are suggested to participate in airway Inflammatory response by e xpressing various cytokines including RANTES; however, the intracellular si gnal that regulates RANTES expression has not been determined. In the prese nt study we examined the role of p38 mitogen-activated protein (MAP) kinase , extracellular signal-regulated kinase (Erk), and c-Jun-NH2-terminal kinas e (JNK) in RANTES production by IV-infected human bronchial epithelial cell s. The results showed that IV infection induced increases in p38 MAP kinase , and Erk and JNK phosphorylation add. activity, SE 203580, PD 98059, and C EP-1347 attenuated IV-infection induced p38 MAP kinase activity, Erk activi ty, and JNK activity, respectively. SE 203580 and CEP-1347 attenuated RANTE S production by 45.3% and 45.2%, respectively, but a combination of these i nhibitors additively attenuated by 69.1%, In contrast, PD 95059 did not att enuate. Anti-IL-1 alpha mAb, anti-IL-IB mAb, anti-TNF-alpha mAb, anti-IL-8 mAb, anti-IFN-beta mAb, anti-RANTES mAb, and a combination of these mAbs di d not affect IV infection-induced increases in p38 MAP kinase, Erk, and JNK phosphorylation, indicating that each cytokine neutralized by correspondin g Ab was not involved in IV infection-induced phosphorylation of MAP kinase s, N-acetylcysteine (NAC) did not affect IV infection-induced increases in MAP kinase phosphorylation, whereas NAC attenuated RANTES production by 18. 2%, indicating that reactive oxygen species may act as a second messenger l eading to RANTES production via p38 MAP kinase- and JNK-independent pathway . These results indicate that p38 MAP kinase and JNK, at least in part, reg ulate RANTES production by bronchial epithelial cells.