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Glucocorticoid Receptor Interacting Protein-1 Restores Glucocorticoid Responsiveness in Steroid-Resistant Airway Structural Cells

¹ Department of Medicine and the Airways Biology Initiative, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; ² Hospital for Special Surgery and Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York; ³ Syracuse University, School of Education, Syracuse, New York; ⁴ Institute of Lung Health, University of Leicester, Leicester, United Kingdom; and ⁵ Department of Pharmaceutical Sciences, Thomas Jefferson University, Philadelphia, Pennsylvania

Correspondence and requests for reprints should be addressed to Omar Tliba, DVM, Ph.D., Department of Pharmaceutical Sciences, Thomas Jefferson University, Jefferson School of Pharmacy, 130 South 9th Street, Edison 1540-H, Philadelphia, PA 19107-5233. E-mail: omar.tliba{at}jefferson.edu

Glucocorticoid (GC) insensitivity represents a profound challenge in managing patients with asthma. The mutual inhibition of transcriptional activity between GC receptor (GR) and other regulators is one of the mechanisms contributing to GC resistance in asthma. We recently reported that interferon regulatory factor (IRF)-1 is a novel transcription factor that promotes GC insensitivity in human airway smooth muscle (ASM) cells by interfering with GR signaling (Tliba et al., Am J Respir Cell Mol Biol 2008;38:463–472). Here, we sought to determine whether the inhibition of GR function by IRF-1 involves its interaction with the transcriptional co-regulator GR-interacting protein 1 (GRIP-1), a known GR transcriptional co-activator. We here found that siRNA-mediated GRIP-1 depletion attenuated IRF-1–dependent transcription of the luciferase reporter construct and the mRNA expression of an IRF-1–dependent gene, CD38. In parallel experiments, GRIP-1 silencing significantly reduced GR-mediated transactivation activities. Co-immunoprecipitation and GST pull-down assays showed that GRIP-1, through its repression domain, physically interacts with IRF-1 identifying GRIP-1 as a bona fide transcriptional co-activator for IRF-1. Interestingly, the previously reported inhibition of GR-mediated transactivation activities by either TNF- and IFN- treatment or IRF-1 overexpression was fully reversed by increasing cellular levels of GRIP-1. Together, these data suggest that the cellular accumulation of IRF-1 may represent a potential molecular mechanism mediating altered cellular response to GC through the depletion of GRIP-1 from the GR transcriptional regulatory complexes.

Key Words: glucocorticoid • cytokine • airway smooth muscle • IRF-1 • GRIP-1

CLINICAL RELEVANCE In steroid-resistant asthma, inflammatory factors lead to an excess of transcription factors that antagonize steroid signaling via the competition with glucocorticoid receptor (GR)-associated co-activators. We here showed that competition between interferon regulatory factor-1 and GR for GR interacting protein-1 is a novel molecular mechanism promoting steroid dysfunction in inflammatory diseases.