Calcium-calmodulin mediates house dust mite-induced ERK activation and IL-8 production in human respiratory epithelial cells.
BACKGROUND
House dust mites (HDM) have been shown to be important sources of indoor allergens associated with asthma and other allergic conditions. While exogenous proteases from allergens have a direct proinflammatory role in the respiratory tract, the precise mechanisms underlying the release of cytokines from the respiratory epithelium are unclear.


OBJECTIVE
The present study examines that extracellular signal-regulated kinase (ERK) activated downstream of the Ca(2+)-sensitive tyrosine kinase plays an important role in the efficient activation of the HDM-induced IL-8 signaling pathway.


METHODS
We examined the effect of HDM, and the role of the Ca(2+)/calmodulin system and mitogen-activated protein kinases, on IL-8 expression in human lung epithelial cells.


RESULTS
In H292 cells, HDM induced IL-8 release in a time- and/or dose-dependent manner. This IL-8 release was abolished by treatment with intracellular Ca(2+) chelator (BAPTA-AM), but not by EGTA or nifedipine. Calmodulin inhibitor (calmidazolium) and tyrosine kinase inhibitor (genistein) almost completely blocked IL-8 release by HDM. PD98,059, an ERK pathway inhibitor, completely abolished HDM-induced IL-8 release. Moreover, PD98,059, BAPTA-AM, calmidazolium and genistein suppressed the HDM-induced ERK phosphorylation.


CONCLUSIONS
HDM-induced IL-8 production is predominantly regulated by Ca(2+)/calmodulin signaling, and ERK plays an important role in signal transmission for efficient activation of the HDM-induced IL-8 signaling pathway.
Sohn
Myung Hyun
MH
Department of Pediatrics and Institute of Allergy, BK21 Project for Medical Science, Biomolecule Secretion Research Center, Yonsei University College of Medicine, Seoul, Korea.
Lee
Kyung Eun
KE
Kim
Kyung-Won
KW
Kim
Eun-Soo
ES
Park
Jun Young
JY
Kim
Kyu-Earn
KE
D000485:Allergens / Q000009:adverse effects*; D000818:Animals; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D040001:Dermatophagoides farinae / Q000276:immunology*; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005419:Flavonoids; D015870:Gene Expression / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D012313:RNA / Q000235:genetics; D020545:Respiratory Mucosa / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000485:Allergens; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D016209:Interleukin-8; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; C031938:calmidazolium; D004533:Egtazic Acid; D012313:RNA; D019833:Genistein; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one