Involvement of p42/p44 MAPK, JNK, and NF-κB in IL-1β-induced ICAM-1 expression in human pulmonary epithelial cells

Abstract

Interleukin-1β (IL-1β) has been shown to induce the expression of intercellular adhesion molecule-1 (ICAM-1) on airway epithelial cells and contributes to inflammatory responses. However, the mechanisms regulating ICAM-1 expression by IL-1β in human A549 cells was not completely understood. Here, the roles of mitogen-activated protein kinases (MAPKs) and NF-κB pathways for IL-1β-induced ICAM-1 expression were investigated in A549 cells. IL-1β induced expression of ICAM-1 protein and mRNA in a time- and concentration-dependent manner. The IL-1β induction of ICAM-1 mRNA and protein were partially inhibited by U0126 and PD98059 (specific inhibitors of MEK1/2) and SP600125 [a specific inhibitor of c-Jun-N-terminal kinase (JNK)]. U0126 was more potent than other inhibitors to attenuate IL-1β-induced ICAM-1 expression. Consistently, IL-1β stimulated phosphorylation of p42/p44 MAPK and JNK which was attenuated by pretreatment with U0126 or SP600125, respectively. Moreover, transfection with dominant negative mutants of MEK1/2 (MEK K97R) or ERK2 (ERK2 K52R) also attenuated IL-1β-induced ICAM-1 expression. The combination of PD98059 and SP600125 displayed an additive effect on IL-1β-induced ICAM-1 gene expression. IL-1β-induced ICAM-1 expression was almost completely blocked by a specific NF-κB inhibitor helenalin. Consistently, IL-1β stimulated translocation of NF-κB into the nucleus and degradation of IκB-α which was blocked by helenalin, U0126, or SP600125. Taken together, these results suggest that activation of p42/p44 MAPK and JNK cascades, at least in part, mediated through NF-κB pathway is essential for IL-1β-induced ICAM-1 gene expression in A549 cells. These results provide new insight into the mechanisms of IL-1β action that cytokines may promote inflammatory responses in the airway disease. © 2004 Wiley-Liss, Inc.