IL-33 stimulates CXCL8/IL-8 secretion in goblet cells but not normally differentiated airway cells.
BACKGROUND
IL-13, a helper T cell type 2 (Th2) cytokine, transforms cultured airway epithelial cells to goblet cells, and this is not inhibited by corticosteroids. IL-33 stimulates Th2 cytokines and is highly expressed in airways of persons with asthma. The effect of IL-33 on goblet cell differentiation and cytokine secretion has not been described.


OBJECTIVE
We examined the effect of IL-33 on CXCL8/IL-8 secretion from goblet or normally differentiated human bronchial epithelial (NHBE) cells and signalling pathways associated with IL-33 activation in these cells.


METHODS
Normal human bronchial epithelial cells were grown to goblet or normally differentiated ciliated cell phenotype at air-liquid interface in the presence or absence of IL-13. After 14 days, differentiated cells were exposed to IL-33 for 24 h.


RESULTS
CXCL8/IL-8 secretion into the apical (air) side of the goblet cells was greater than from normally differentiated cells (P < 0.01), and IL-33 stimulated apical CXCL8/IL-8 release from goblet cells, but not from normally differentiated cells (P < 0.01). IL-33 increased ERK 1/2 phosphorylation in goblet cells (P < 0.05), and PD98059, a MAPK/ERK kinase inhibitor, attenuated IL-33-stimulated CXCL8/IL-8 secretion from goblet cells (P < 0.001). IL-13 induced ST2 mRNA (P < 0.02) and membrane-bound ST2 protein expression on the apical side surface of goblet cells compared with normally differentiated cells, and neutralization with anti-ST2R antibody attenuated IL-33-induced apical CXCL8/IL-8 secretion from goblet cells (P < 0.02).


CONCLUSIONS
Goblet cells secrete CXCL8/IL-8, and this is increased by IL-33 through ST2R-ERK pathway, suggesting a mechanism for enhanced airway inflammation in the asthmatic airway with goblet cell metaplasia.
Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
T
T
Tanabe
T
T
Shimokawaji
S
S
Kanoh
B K
BK
Rubin
D002454:Cell Differentiation / Q000187:drug effects; D015870:Gene Expression; D020397:Goblet Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D018793:Interleukin-13 / Q000494:pharmacology; D000067596:Interleukin-33; D016209:Interleukin-8 / Q000096:biosynthesis*; D007378:Interleukins / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009930:Organic Chemicals / Q000494:pharmacology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*
C079241:IL1RL1 protein, human; C506536:IL33 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D018793:Interleukin-13; D000067596:Interleukin-33; D016209:Interleukin-8; D007378:Interleukins; D009930:Organic Chemicals; C466090:PD 98058; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
IL-13; Th2 cytokine; airway; asthma; goblet cell hyperplasia; mucin; normal human bronchial epithelial cell