This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 200510-1672OCv1 174/12/1299    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jaradat, M. Articles by Jetten, A. M. Search for Related Content PubMed PubMed Citation Articles by Jaradat, M. Articles by Jetten, A. M.

Modulatory Role for Retinoid-related Orphan Receptor in Allergen-induced Lung Inflammation

Cell Biology Section, Laboratory of Respiratory Biology, and Microarray Group, Laboratory of Experimental Pathology, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park; and Pulmonary Immunobiology Laboratory, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina

Correspondence and requests for reprints should be addressed to Anton M. Jetten, Ph.D., Cell Biology Section, Laboratory of Respiratory Biology, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive, Research Triangle Park, NC 27599-7219. E-mail: jetten{at}niehs.nih.gov

Rationale: Nuclear receptors play a critical role in the regulation of inflammation, thus representing attractive targets for the treatment of asthma.

Objective: In this study, we assess the potential regulatory function of retinoid-related orphan receptor (ROR) in the adaptive immune response using ovalbumin (OVA)-induced airway inflammation as a model.

Methods: Allergen-induced inflammation was compared between wild-type (WT) and staggerer (ROR^sg/sg) mice, a natural mutant strain that is deficient in ROR expression.

Measurements and Main Results: Despite robust increases in OVA-specific IgE, ROR^sg/sg mice developed significantly less pulmonary inflammation, mucous cell hyperplasia, and eosinophilia compared with similarly treated WT animals. Induction of Th2 cytokines, including interleukin (IL)-4, IL-5, and IL-13, was also significantly less in ROR^sg/sg mice. Microarray analysis using lung RNA showed increased expression of many genes, previously implicated in inflammation, in OVA-treated WT mice. These include mucin Muc5b, the chloride channel calcium-activated 3 (Clca3), macrophage inflammatory protein (MIP) 1 and 1, eotaxin-2, serum amyloid A3 (Saa3), and insulin-like growth factor 1 (Igf1). These genes were induced to a greater extent in OVA-treated WT mice relative to ROR^sg/sg mice.

Conclusions: Our study demonstrates that mice deficient in ROR exhibit an attenuated allergic inflammatory response, indicating that ROR plays a critical role in the development of Th2-driven allergic lung inflammation in mice, and suggests that this nuclear receptor should be further evaluated as a potential asthma target.

Key Words: asthma • inflammation • lung • nuclear receptor

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Nuclear receptors with antiinflammatory effects are promising pharmacological targets, and may offer novel therapeutic strategies for asthma. What This Study Adds to the Field Retinoid-related orphan receptor (ROR) plays a critical role in the development of allergic lung inflammation, suggesting that this receptor should be further evaluated as a potential asthma target.

 

This article has been cited by other articles:

				K. Smoak, J. Madenspacher, S. Jeyaseelan, B. Williams, D. Dixon, K. R. Poch, J. A. Nick, G. S. Worthen, and M. B. Fessler Effects of Liver X Receptor Agonist Treatment on Pulmonary Inflammation and Host Defense J. Immunol., March 1, 2008; 180(5): 3305 - 3312. [Abstract] [Full Text] [PDF]

				H. S. Kang, M. Angers, J. Y. Beak, X. Wu, J. M. Gimble, T. Wada, W. Xie, J. B. Collins, S. F. Grissom, and A. M. Jetten Gene expression profiling reveals a regulatory role for ROR{alpha} and ROR{gamma} in phase I and phase II metabolism Physiol Genomics, October 19, 2007; 31(2): 281 - 294. [Abstract] [Full Text] [PDF]

				W. C. Moore and S. P. Peters Update in Asthma 2006 Am. J. Respir. Crit. Care Med., April 1, 2007; 175(7): 649 - 654. [Full Text] [PDF]