IL-13-induced Clara cell secretory protein expression in airway epithelium: role of EGFR signaling pathway.
Previous work showed that the Th2 cytokine interleukin (IL)-13 induces goblet cell metaplasia via an indirect mechanism involving the expression and subsequent activation of epidermal growth factor receptor (EGFR). Because Clara cell secretory protein (CCSP) expression has been reported in cells that express mucins, we examined the effect of IL-13 on CCSP gene and protein expression in pathogen-free rat airways and in pulmonary mucoepidermoid NCI-H292 cells. Intratracheal instillation of IL-13 induced CCSP mRNA in epithelial cells without cilia within 8-16 h, maximal between 24 and 48 h; CCSP immunostaining increased in a time-dependent fashion, maximal at 48 h. The CCSP immunostaining was localized in nongranulated secretory cells and goblet cells and in the lumen. Pretreatment with the selective EGFR tyrosine kinase inhibitor BIBX1522, cyclophosphamide (an inhibitor of bone marrow leukocyte mobilization), or a blocking antibody to IL-8 prevented CCSP staining. Treatment of NCI-H292 cells with the EGFR ligand transforming growth factor-alpha, but not with IL-13 alone, induced CCSP gene and protein expression. Selective EGFR tyrosine kinase inhibitors, BIBX1522 and AG1478, prevented CCSP expression in NCI-H292 cells, but the platelet-derived growth factor receptor tyrosine kinase inhibitor AG1295 had no effect. These findings indicate that IL-13 induces CCSP expression via an EGFR- and leukocyte-dependent pathway.
Kim
Suil
S
Cardiovascular Research Institute and Department of Medicine, University of California, San Francisco, California 94143-0130, USA.
Shim
Jae Jeong
JJ
Burgel
Pierre-Regis
PR
Ueki
Iris F
IF
Dao-Pick
Trang
T
Tam
Dominic Cheng-Wei
DC
Nadel
Jay A
JA
D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology; D066246:ErbB Receptors / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D020397:Goblet Cells / Q000737:chemistry / Q000502:physiology; D018793:Interleukin-13 / Q000494:pharmacology*; D008297:Male; D009504:Neutrophils / Q000166:cytology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011506:Proteins / Q000032:analysis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D020545:Respiratory Mucosa / Q000737:chemistry / Q000187:drug effects* / Q000276:immunology; D015398:Signal Transduction / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D014598:Uteroglobin
D018793:Interleukin-13; D011506:Proteins; D012333:RNA, Messenger; C556391:Scgb1a1 protein, rat; D016211:Transforming Growth Factor alpha; D014598:Uteroglobin; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases