IL-13 induces mucin production by stimulating epidermal growth factor receptors and by activating neutrophils.
Mucus hypersecretion contributes to the morbidity and mortality in acute asthma. Both T helper 2 (Th2) cytokines and epidermal growth factor receptor (EGFR) signaling have been implicated in allergen-induced goblet cell (GC) metaplasia. Present results show that a cascade of EGFR involving neutrophils is implicated in interleukin (IL)-13-induced mucin expression in GC. Treatment with a selective EGFR tyrosine kinase inhibitor prevented IL-13-induced GC metaplasia dose dependently and completely. Instillation of IL-13 also induced tumor necrosis factor-alpha protein expression, mainly in infiltrating neutrophils. Control airway epithelium contained few leukocytes, but intratracheal instillation of IL-13 resulted in time-dependent leukocyte recruitment by IL-13-induced IL-8-like chemoattractant expression in airway epithelium. Pretreatment with an inhibitor of leukocytes in the bone marrow (cyclophosphamide) or with a blocking antibody to IL-8 prevented both IL-13-induced leukocyte recruitment and GC metaplasia. These findings indicate that EGFR signaling is involved in IL-13-induced mucin production. They suggest a potential therapeutic role for inhibitors of the EGFR cascade in the hypersecretion that occurs in acute asthma.
Shim
J J
JJ
Cardiovascular Research Institute, University of California, San Francisco, California 94132-0130, USA.
Dabbagh
K
K
Ueki
I F
IF
Dao-Pick
T
T
Burgel
P R
PR
Takeyama
K
K
Tam
D C
DC
Nadel
J A
JA
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D003520:Cyclophosphamide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism*; D020397:Goblet Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D018793:Interleukin-13 / Q000494:pharmacology*; D016209:Interleukin-8 / Q000276:immunology; D008297:Male; D008679:Metaplasia; D009077:Mucins / Q000096:biosynthesis*; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D011916:Rats, Inbred F344; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013047:Specific Pathogen-Free Organisms; D018418:Th2 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D019138:Antibodies, Blocking; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D018793:Interleukin-13; D016209:Interleukin-8; D009077:Mucins; D014409:Tumor Necrosis Factor-alpha; D003520:Cyclophosphamide; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases