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* Research Center for Genetic Medicine and
Division of Pulmonary Medicine, Children’s National Medical Center, Washington, DC 20010; and
Department of Pediatrics and
Department of Biochemistry and Molecular Biology, George Washington University School of Medicine and Health Services, Washington, DC 20037
Airway inflammation and mucus hypersecretion/overproduction/obstruction are pathophysiological characteristics of cystic fibrosis, asthma, and chronic obstructive pulmonary disease. Up-regulation of airway mucin genes by inflammatory/immune response mediators is one of the major contributors to mucin overproduction. IL-8, a potent proinflammatory mediator and neutrophil chemoattractant, is present at high levels in the airway secretions of such patients. In this study, the effects of IL-8 on expression of two major airway mucin genes, MUC5AC and MUC5B, were evaluated. IL-8 increased the mRNA abundance of both mucin genes in two human respiratory tract-derived cell lines (A549 and NCI-H292) in a time- and concentration-dependent manner. IL-8 also increased MUC5AC and MUC5B mRNA levels in primary normal differentiated human bronchial epithelial cells, with a high concentration of IL-8 required to increase MUC5B mRNA levels. IL-8 did not transcriptionally up-regulate MUC5AC gene expression, but rather increased the stability of the MUC5AC transcript, suggesting regulation at the posttranscriptional level. In addition, IL-8 altered the levels of RNA-binding proteins to specific domains in the 3'-untranslated region of the MUC5AC transcript. Taken together, these data indicate that the IL-8-induced binding of RNA-binding proteins to the 3'-untranslated region of MUC5AC is a potential mechanism for regulating MUC5AC gene expression at the posttranscriptional level, thus suggesting a new role whereby IL-8 sustains mucin gene expression in inflamed airways.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by National Institutes of Health Grant HL33152 and by a grant from the Cystic Fibrosis Foundation (to M.C.R.).
2 Some of these data were originally presented at the 1999 and 2005 North American Cystic Fibrosis conferences.
3 Current address: Department of Pediatrics, Georgetown University, Washington, DC 20007
4 Address correspondence and reprint requests to Dr. Mary C. Rose, Research Center for Genetic Medicine, Children’s National Medical Center, 111 Michigan Avenue, Washington, DC 20010. E-mail address: mrose{at}cnmc.org
5 Abbreviations used in this paper: CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; HBE, human bronchial epithelial; MUC, mucin; NE, neutrophil elastase; REMSA, RNA electrophoretic shift mobility assay; RBP, RNA-binding protein; UTR, untranslated region.
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