title: ORMDL3 is an inducible lung epithelial gene regulating metalloproteases, chemokines, OAS, and ATF6.
abstract: Orosomucoid like 3 (ORMDL3) has been strongly linked with asthma in genetic association studies, but its function in asthma is unknown. We demonstrate that in mice ORMDL3 is an allergen and cytokine (IL-4 or IL-13) inducible endoplasmic reticulum (ER) gene expressed predominantly in airway epithelial cells. Allergen challenge induces a 127-fold increase in ORMDL3 mRNA in bronchial epithelium in WT mice, with lesser 15-fold increases in ORMDL-2 and no changes in ORMDL-1. Studies of STAT-6-deficient mice demonstrated that ORMDL3 mRNA induction highly depends on STAT-6. Transfection of ORMDL3 in human bronchial epithelial cells in vitro induced expression of metalloproteases (MMP-9, ADAM-8), CC chemokines (CCL-20), CXC chemokines (IL-8, CXCL-10, CXCL-11), oligoadenylate synthetases (OAS) genes, and selectively activated activating transcription factor 6 (ATF6), an unfolded protein response (UPR) pathway transcription factor. siRNA knockdown of ATF-6α in lung epithelial cells inhibited expression of SERCA2b, which has been implicated in airway remodeling in asthma. In addition, transfection of ORMDL3 in lung epithelial cells activated ATF6α and induced SERCA2b. These studies provide evidence of the inducible nature of ORMDL3 ER expression in particular in bronchial epithelial cells and suggest an ER UPR pathway through which ORMDL3 may be linked to asthma.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Miller
authors.forename: Arvin B
authors.initials: AB
authors.lastname: Tam
authors.forename: Jae Youn
authors.initials: JY
authors.lastname: Cho
authors.forename: Taylor A
authors.initials: TA
authors.lastname: Doherty
authors.forename: Alexa
authors.initials: A
authors.lastname: Pham
authors.forename: Naseem
authors.initials: N
authors.lastname: Khorram
authors.forename: Peter
authors.initials: P
authors.lastname: Rosenthal
authors.forename: James L
authors.initials: JL
authors.lastname: Mueller
authors.forename: Hal M
authors.initials: HM
authors.lastname: Hoffman
authors.forename: Maho
authors.initials: M
authors.lastname: Suzukawa
authors.forename: Maho
authors.initials: M
authors.lastname: Niwa
authors.forename: David H
authors.initials: DH
authors.lastname: Broide
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics / Q000378:metabolism*; D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D045726:Metalloproteases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000494:pharmacology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics
chemical_list: D051702:Activating Transcription Factor 6; D018925:Chemokines; D018793:Interleukin-13; D008565:Membrane Proteins; C464399:ORMDL3 protein, human; C583840:ORMDL3 protein, mouse; D015847:Interleukin-4; D010047:Ovalbumin; D015088:2',5'-Oligoadenylate Synthetase; D045726:Metalloproteases