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Inhibition of COX-2 by celecoxib enhances glucocorticoid receptor function

Molecular Psychiatry volume 10, pages 426–428 (2005)Cite this article

Sir—Celecoxib is a widely used nonsteroidal anti-inflammatory agent that acts through selective inhibition of COX-2. Here we demonstrate that celecoxib also significantly increases nuclear localization of the glucocorticoid receptor (GR), increases GR binding to its DNA responsive element and enhances GR-mediated gene transcription in association with inhibition of p38 MAP kinase. These results expand the intracellular targets of COX-2 inhibitors while widening their potential clinical application to multiple disorders associated with impaired GR function including major depression.

Glucocorticoids play an essential role in shaping and eventually restraining physiological responses to environmental stressors, including early, innate, immune responses (inflammation); activation of the sympathetic nervous system and stimulation of neuroendocrine pathways, all of which are capable of producing a host of adverse health outcomes if allowed to continue unabated after stressor cessation.1 A number of diseases including certain autoimmune, infectious and inflammatory disorders as well as a subgroup of neuropsychiatric disorders such as major depression have been associated with decreased responsiveness to glucocorticoids and impaired functioning of the GR.2, 3 One potential mediator of disrupted GR function in these diseases is proinflammatory cytokines.3 Each of these disorders has been characterized by increased circulating and/or tissue expression of proinflammatory cytokines. Moreover, proinflammatory cytokines through their signaling pathways have been found to negatively regulate GR function. For example, IL-1 alpha activation of p38 MAPK pathways has been shown to decrease GR DNA binding and GR-mediated gene transcription.4 Similar decreases in GR activity have been found following activation of JNK and NF-kB inflammatory signaling pathways.5, 6

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Acknowledgements

This work was supported in part by grants from the National Institute of Mental Health (MH-067041) and the Emory University Research Committee Award.

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  1. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA

    F Hu, X Wang, T W W Pace, H Wu & A H Miller

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  1. F Hu
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  2. X Wang
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  3. T W W Pace
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  4. H Wu
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Correspondence to A H Miller.

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Hu, F., Wang, X., Pace, T. et al. Inhibition of COX-2 by celecoxib enhances glucocorticoid receptor function. Mol Psychiatry 10, 426–428 (2005). https://doi.org/10.1038/sj.mp.4001644

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