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This Article Full Text Full Text (PDF) All Versions of this Article: 297/1/L164    most recent 90453.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by White, S. R. Articles by Fu, X. PubMed PubMed Citation Articles by White, S. R. Articles by Fu, X.

Insulin receptor substrate-1/2 mediates IL-4-induced migration of human airway epithelial cells

Departments of ¹Medicine and ³Pediatrics, University of Chicago, Chicago, Illinois; and ²Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, North Carolina

Submitted 21 August 2008 ; accepted in final form 13 May 2009

Migration of airway epithelial cells (AEC) is an integral component of airway mucosal repair after injury. The inflammatory cytokine IL-4, abundant in chronic inflammatory airways diseases such as asthma, stimulates overproduction of mucins and secretion of chemokines from AEC; these actions enhance persistent airway inflammation. The effect of IL-4 on AEC migration and repair after injury, however, is not known. We examined migration in primary human AEC differentiated in air-liquid interface culture for 3 wk. Wounds were created by mechanical abrasion and followed to closure using digital microscopy. Concurrent treatment with IL-4 up to 10 ng/ml accelerated migration significantly in fully differentiated AEC. As expected, IL-4 treatment induced phosphorylation of the IL-4 receptor-associated protein STAT (signal transducer and activator of transcription)6, a transcription factor known to mediate several IL-4-induced AEC responses. Expressing a dominant negative STAT6 cDNA delivered by lentivirus infection, however, failed to block IL-4-stimulated migration. In contrast, decreasing expression of either insulin receptor substrate (IRS)-1 or IRS-2 using a silencing hairpin RNA blocked IL-4-stimulated AEC migration completely. These data demonstrate that IL-4 can accelerate migration of differentiated AEC after injury. This reparative response does not require STAT6 activation, but rather requires IRS-1 and/or IRS-2.

epithelium; interleukin-4; STAT6; IRS-1; IRS-2