IL-8 regulates mucin gene expression at the posttranscriptional level in lung epithelial cells.
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.
Bautista
Maria V
MV
Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC 20010, USA.
Chen
Yajun
Y
Ivanova
Vessela S
VS
Rahimi
Michael K
MK
Watson
Alan M
AM
Rose
Mary C
MC
D002478:Cells, Cultured; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D016209:Interleukin-8 / Q000502:physiology*; D008168:Lung / Q000166:cytology*; D055271:Mucin 5AC / Q000096:biosynthesis / Q000235:genetics; D055257:Mucin-5B / Q000096:biosynthesis / Q000235:genetics; D009077:Mucins / Q000096:biosynthesis* / Q000235:genetics; D020871:RNA Stability / Q000276:immunology*; D012333:RNA, Messenger / Q000032:analysis
D016209:Interleukin-8; D055271:Mucin 5AC; D055257:Mucin-5B; D009077:Mucins; D012333:RNA, Messenger