Mucus hypersecretion is an important characteristic feature of the pathogenesis of allergy. Although interleukin (IL)‐4 is known to be an inflammatory mediator in respiratory diseases, the mechanism by which IL‐4 induces MUC5AC gene expression has not been fully explored. The aim of this study was to investigate the mechanism by which IL‐4 induces MUC5AC gene expression in the airway. We examined the role of mitogen‐activated protein kinase (MAPK) signaling on MUC5AC gene expression in airway epithelium. We showed that phosphorylation of ERK1/2 increased after treatment of cells with IL‐4, whereas phosphorylation of p38 and JNK was not detected. In addition, pharmacologic and genetic inhibition of ERK1/2 abolished IL‐4‐induced MUC5AC gene expression. Moreover, we investigated the activation of p90 ribosomal S6 kinase 1 (RSK1) as a downstream signaling target of ERK1/2 in IL‐4 signaling. The activation of RSK1 was prevented by pretreatment with PD98059 or plasmid expressing a MEK1 dominant‐negative mutant. We also found that RSK1 mediated the IL‐4‐induced phosphorylation of cAMP response element‐binding protein (CREB) and the transcription of MUC5AC. Furthermore, the cAMP‐response element (CRE) in the MUC5AC promoter appears to be important for IL‐4‐induced MUC5AC gene expression in NCI‐H292 cells. J. Cell. Biochem. 108: 974–981, 2009. © 2009 Wiley‐Liss, Inc.