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Targeted Identification of Glucocorticoid-attenuated Response Genes

In Vitro and in Vivo Models

Department of Pediatrics, Department of Biological Chemistry, and Department of Molecular Pharmacology, David Geffen School of Medicine, and Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California

Correspondence and requests for reprints should be addressed to Jeffrey B. Smith, M.D., Pediatrics/Neonatology, UCLA Center for the Health Sciences, B2-325A, 10833 Le Conte Avenue, Los Angeles, CA 90095. E-mail: JBSmith{at}ucla.edu

Glucocorticoids attenuate the induction of numerous inflammatory mediators. We hypothesized that a targeted screening for genes with these regulatory characteristics, called glucocorticoid-attenuated response genes (GARGs), would be an efficient way to identify genes participating in glucocorticoid-sensitive inflammatory processes. An initial application of this idea, using an in vitro model, identified 12 cDNAs induced by LPS and attenuated by dexamethasone, including a new chemokine designated LIX. In vivo studies demonstrated that endotoxemia-induced lung mRNA expression of LIX, but not of two related chemokines, is markedly enhanced by adrenalectomy and attenuated by dexamethasone. This work provided the basis for an in vivo screening project that identified 36 GARG cDNAs induced in the lung during endotoxemia. The majority represent genes of unknown function, or genes not previously implicated in the pulmonary response to inflammation. Four encode previously undescribed proteins, including a chemokine, a member of a family of guanylate-binding proteins, a 2'–5' oligoadenylate synthetase–like protein, and a novel lung-inducible Neuralized-related C3HC4 RING protein (LINCR). Our results indicate that glucocorticoid-attenuated response genes are much more diverse than originally anticipated. Future studies using microarrays in this and other inflammation models may identify many additional glucocorticoid-regulated genes potentially important in inflammatory diseases.

Key Words: asthma • chronic obstructive pulmonary disease • glucocorticoid-sensitive inflammation

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