Expression and regulation of a disintegrin and metalloproteinase (ADAM) 8 in experimental asthma.
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 and Aspergillus fumigatus) we uncovered the involvement of ADAM8, a member of a disintegrin and metalloproteinase (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 pharmacologic delivery of interleukin (IL)-4 or IL-13 to the lungs resulted in a marked increase of ADAM8 expression. Gene-targeted mice studies revealed that ovalbumin-induced ADAM8 was largely dependent upon signal transducer and activator of transcription (STAT) 6 and the IL-4 receptor alpha-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.
King
Nina E
NE
Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinatti College of Medicine, Cincinnati, OH 45229, USA.
Zimmermann
Nives
N
Pope
Samuel M
SM
Fulkerson
Patricia C
PC
Nikolaidis
Nikolaos M
NM
Mishra
Anil
A
Witte
David P
DP
Rothenberg
Marc E
ME
D051722:ADAM Proteins; D000485:Allergens; D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics*; D001249:Asthma / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D001483:Base Sequence / Q000235:genetics; D001980:Bronchi / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D018793:Interleukin-13 / Q000235:genetics / Q000494:pharmacology; D015847:Interleukin-4 / Q000235:genetics / Q000494:pharmacology; D008168:Lung / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D008666:Metalloendopeptidases / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
D000485:Allergens; D015703:Antigens, CD; D018793:Interleukin-13; D008565:Membrane Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4; D051722:ADAM Proteins; C489402:Adam8 protein, mouse; D008666:Metalloendopeptidases