IL-4 induces mucin gene expression and goblet cell metaplasia in vitro and in vivo.
Goblet cell metaplasia and mucus hypersecretion are important features in the pathogenesis of asthma. The cytokine IL-4 has been shown to play a role in animal models of asthma, where it induces Th2 lymphocyte differentiation and B lymphocyte IgE class switch. IL-4 has also been implicated in the differentiation of goblet cells via effects on lymphocytes and eosinophils. In this study we hypothesized that IL-4 induces airway epithelial cell mucin gene expression and mucous glycoconjugate production by direct action on these cells. In vitro, cultured airway epithelial cells (NCI-H292) expressed IL-4R constitutively, and IL-4 (10 ng/ml) induced MUC2 gene expression and mucous glycoconjugate production. In vivo, mouse airway epithelial cells expressed IL-4R constitutively, and IL-4 (250 ng) increased MUC5 gene expression and Alcian blue/periodic acid-Schiff-positive staining at 24 h; IL-4 did not increase inflammatory cell numbers in airway tissue or in bronchoalveolar lavage. TNF-alpha and IL-1beta levels in bronchoalveolar lavage were not increased in response to IL-4 instillation. These results indicate that airway epithelial cells express IL-4R constitutively and that IL-4 directly induces the differentiation of epithelium into mucous glycoconjugate-containing goblet cells.
Dabbagh
K
K
Cardiovascular Research Institute and Departments of Medicine and Physiology, University of California, San Francisco, CA 94143, USA. janadel@itsa.ucsh.edu
Takeyama
K
K
Lee
H M
HM
Ueki
I F
IF
Lausier
J A
JA
Nadel
J A
JA
D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000473:pathology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002460:Cell Line; D005786:Gene Expression Regulation; D006001:Glycoconjugates / Q000096:biosynthesis; D020397:Goblet Cells / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D007375:Interleukin-1 / Q000032:analysis; D015847:Interleukin-4 / Q000494:pharmacology*; D008297:Male; D008679:Metaplasia; D051379:Mice; D008807:Mice, Inbred BALB C; D055271:Mucin 5AC; D055262:Mucin-2; D009077:Mucins / Q000096:biosynthesis* / Q000235:genetics; D019948:Receptors, Interleukin-4 / Q000302:isolation & purification*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D006001:Glycoconjugates; D007375:Interleukin-1; C524625:MUC2 protein, human; C524678:MUC5AC protein, human; C524626:Muc2 protein, mouse; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D055262:Mucin-2; D009077:Mucins; D019948:Receptors, Interleukin-4; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4