Insulin receptor substrate-1/2 mediates IL-4-induced migration of human airway epithelial cells.
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.
White
Steven R
SR
Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA. swhite@medicine.bsd.uchicago.edu
Martin
Linda D
LD
Abe
Mark K
MK
Marroquin
Bertha A
BA
Stern
Randi
R
Fu
Xiaoying
X
D000388:Air; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D018076:DNA, Complementary / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D005799:Genes, Dominant; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D015847:Interleukin-4 / Q000494:pharmacology*; D008168:Lung / Q000166:cytology* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism
D018076:DNA, Complementary; D055504:Insulin Receptor Substrate Proteins; D034741:RNA, Small Interfering; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015847:Interleukin-4