Published ahead of print on April 15, 2004, doi:10.1165/rcmb.2004-0026OC
Am. J. Respir. Cell Mol. Biol., Volume 31, Number 3, September 2004, 257-265
A more recent version of this article appeared on September 1, 2004
Submitted on January 30, 2004
Revised on April 14, 2004
Expression and regulation of a disintegrin and metalloproteinase (ADAM)8 in experimental asthma
Nina E King1, Nives Zimmermann1, Samuel M Pope1, Patricia C Fulkerson1, Nikolaos M Nikolaidis1, Anil Mishra1, David P Witte2, and Marc E Rothenberg1*
1 Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA,
2 Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
* To whom correspondence should be addressed. E-mail: rothenberg{at}chmcc.org.
Asthma, a complex chronic inflammatory pulmonary disorder, is on the rise despite intense ongoing research. To elucidate novel pathways involved in asthma pathogenesis, we used transcript expression profiling in a murine model of asthma. Employing asthma models induced by different allergens (ovalbumin [OVA] and Aspergillus fumigatus) we uncovered the involvement of ADAM8, a member of a metalloproteinase and disintegrin (ADAM) family. In situ hybridization of mouse lungs revealed strong ADAM8 induction in peribronchial and perivascular inflammatory cells as well as in bronchiolar epithelial cells following allergen challenge. Sequence analysis of lung ADAM8 cDNA identified a novel splice variant of ADAM8, that contained an additional exon in juxtaposition to the transmembrane domain. Allergen-induced ADAM8 mRNA accumulation in the lung was dose- and time-dependent. Transgenic or pharmacological delivery of IL-4 or IL-13 to the lungs resulted in a marked increase of ADAM8 expression. Gene-targeted mice studies revealed that OVA-induced ADAM8 was largely dependent upon STAT6 and the IL-4 receptor (R) -chain. Thus, ADAM8 is an allergen-, IL-4, and IL-13-induced gene in the experimental asthmatic lung. Taken together with the role of ADAM33 in asthma, these results suggest that allergic lung responses involve the interplay of diverse members of the ADAM family.
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