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Background  The gene  ORMDL3  was shown to be associated with early-onset asthma susceptibility in multiple independent genome-wide and candidate-gene association studies. Asthmatic patients have elevated expression levels of this gene.  ORMDL3  encodes a transmembrane protein localized in the endoplasmic reticulum (ER) that may be involved in ER stress and inflammation. It is essential to validate the genetic associations linking  ORMDL3  with asthma through functional studies that confirm the biological relevance of this gene in disease. We investigated the effects of manipulating  ORMDL3  expression levels  in vitro  in airway cells on innate immune inflammatory responses, ER stress and activation of the unfolded protein response (UPR).    Methods   ORMDL3  expression levels were manipulated in airway cells using an overexpression plasmid and siRNA technologies. Successful modulation of ORMDL3 was confirmed at both the gene and protein level. The functional impact of modulation of  ORMDL3  expression levels on inflammatory responses and activation of the UPR were quantified using complementary cellular and molecular immunology techniques.    Results  Cells with altered  ORMDL3  levels responded equally well to innate immune stimuli and produced similar levels of pro-inflammatory cytokines compared to wild-type cells. Treatment with ER stress inducers, thapsigargin and tunicamycin, resulted in activation of the unfolded protein response (UPR). However, we observed no difference in UPR activation in cells with  ORMDL3  knockdown compared to cells with normal  ORMDL3  levels.    Conclusions  Our results suggest that  ORMDL3  variation in the airway epithelium is unlikely to play a significant role in modulating innate immune responses and the UPR in the lung.

allergy, asthma and clinical immunology/allergy, asthma, and clinical immunology

Functional analysis of the impact of ORMDL3 expression on inflammation and activation of the unfolded protein response in human airway epithelial cells