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The purpose of this research was to elucidate the pathway\/mechanisms that lead to TCDD-induced gene expression in both primary normal human bronchial epithelial cells and an immortalized cell line, HBE1, under air\u2013liquid interface conditions. TCDD exposure induced a time-dependent elevation of MUC5AC mRNA and protein synthesis, and cytochrome p450 1A1 (CYP1A1) expression in these cells. Treatment with an aryl hydrocarbon receptor antagonist had no effect on TCDD-induced MUC5AC expression, but significantly suppressed CYP1A1 induction. However, treatments with inhibitors of signaling pathways and the expression of dominant negative mutants of epidermal growth factor receptor (EGFR), extracellular signal\u2013regulated kinase (ERK) and p38, but not the inhibition of c-Jun N-terminal kinase pathway, abrogated MUC5AC induction, but not that of CYP1A1. These effects also occurred at the MUC5AC promoter\u2013reporter level using the chimeric construct for a transient transfection study. Western blot analysis confirmed the phosphorylation of activated EGFR, ERK, and p38 signaling molecules, but not the c-Jun N-terminal kinase, in cells after TCDD exposure. Specificity protein 1 (Sp1) phosphorylation also occurred in cells after TCDD exposure. Both MUC5AC expression and the promoter activity were inhibited by mithramycin A, an inhibitor specific to Sp1-based transcription. These results lead to the conclusion that TCDD induced MUC5AC expression through a noncanonical aryl hydrocarbon receptor\u2013independent, EGFR\/ERK\/p38\u2013mediated signaling pathway\u2013mediated\/Sp1-based transcriptional mechanism.<\/jats:p>","DOI":"10.1165\/rcmb.2010-0313oc","type":"journal-article","created":{"date-parts":[[2010,10,22]],"date-time":"2010-10-22T21:00:52Z","timestamp":1287781252000},"page":"270-276","source":"Crossref","is-referenced-by-count":23,"title":["2,3,7,8-Tetrachlorodibenzo-p-dioxin\u2013Induced\n                    <i>MUC5AC<\/i>\n                    Expression"],"prefix":"10.1093","volume":"45","author":[{"given":"Yong C.","family":"Lee","sequence":"first","affiliation":[{"name":"Center for Comparative Respiratory Biology and Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen L.","family":"Oslund","sequence":"additional","affiliation":[{"name":"Center for Comparative Respiratory Biology and Medicine"},{"name":"Department 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