Rationale: Airway smooth muscle cells (ASMC) are a source of inflammatory chemokines that may propagate airway inflammatory responses. Objectives: We investigated the production of the CXC chemokine, growth-related oncogene protein- (GRO-), from ASMC induced by cytokines and the role of mitogen-activated protein kinase (MAPK) and NF-B pathways. Methods: ASMC were cultured from human airways and grown to confluence and exposed to cytokines, IL-1 and TNF-following growth arrest. Results: GRO- release, measured by ELISA, was increased by >50-fold following IL-1 (0.1 ng ml-¹) or 5-fold after TNF- (1 ng ml-¹) in a dose- and time-dependent manner. IL-1 and TNF- also induced GRO-mRNA expression. Supernatants from IL-1-stimulated ASMCs were chemotactic for neutrophils; this effect was inhibited by anti-GRO blocking antibody. AS602868, an inhibitor of inhibitory B kinase-2 (IKK-2), and PD98059, an inhibitor of extracellular signal-regulated kinase (ERK) inhibited GRO- release and mRNA expression while SP600125, an inhibitor of c-jun N-terminal kinase (JNK), reduced GRO-release without effect on mRNA expression. SB203580, an inhibitor of p38 MAPK, had no effect. AS602868 but not PD98059 or SP600125 inhibited p65 DNA-binding induced by IL-1 and TNF-. Using chromatin immunoprecipitation assay, IL-1- and TNF--enhanced p65 binding to the GRO-a promoter, which was inhibited by AS602868. Conclusions: IL-1- and TNF--stimulated expression of GRO- from ASMC is regulated by independent pathways involving NF-B activation and ERK and JNK pathways. GRO- released from ASMC participates in neutrophil chemotaxis.