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Sci. Signal., 12 October 2010
Vol. 3, Issue 143, p. ra74
[DOI: 10.1126/scisignal.2001077]

RESEARCH ARTICLES

Sexually Dimorphic Actions of Glucocorticoids Provide a Link to Inflammatory Diseases with Gender Differences in Prevalence

Danielle Duma1, Jennifer B. Collins2, Jeff W. Chou3, and John A. Cidlowski1*

1Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, MD F3-07, P.O. Box 12233, Research Triangle Park, NC 27709, USA.
2Microarray Facility, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, 111 TW Alexander Drive, Research Triangle Park, NC 27709, USA.
3Department of Biostatistical Sciences, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.

Abstract: Males and females show differences in the prevalence of many major diseases that have important inflammatory components to their etiology. These gender-specific diseases, which include autoimmune diseases, hepatocellular carcinoma, diabetes, and osteoporosis, are largely considered to reflect the actions of sex hormones on the susceptibility to inflammatory stimuli. However, inflammation reflects a balance between pro- and anti-inflammatory signals, and investigation of gender-specific responses to the latter has been neglected. Glucocorticoids are the primary physiological anti-inflammatory hormones in mammals, and synthetic derivatives of these hormones are prescribed as anti-inflammatory agents, irrespective of patient gender. We explored the possibility that sexually dimorphic actions of glucocorticoid regulation of gene expression may contribute to the dimorphic basis of inflammatory disease by evaluating the rat liver, a classic glucocorticoid-responsive organ. Surprisingly, glucocorticoid administration expanded the set of hepatic sexually dimorphic genes. Eight distinct patterns of glucocorticoid-regulated gene expression were identified, which included sex-specific genes. Our experiments also defined specific genes with altered expression in response to glucocorticoid treatment in both sexes, but in opposite directions. Pathway analysis identified sex-specific glucocorticoid-regulated gene expression in several canonical pathways involved in susceptibility to and progression of diseases with gender differences in prevalence. Moreover, a comparison of the number of genes involved in inflammatory disorders between sexes revealed 84 additional glucocorticoid-responsive genes in the male, suggesting that the anti-inflammatory actions of glucocorticoids are more effective in males. These gender-specific actions of glucocorticoids in liver were substantiated in vivo with a sepsis model of systemic inflammation.

* To whom correspondence should be addressed. E-mail: cidlows1{at}niehs.nih.gov

Citation: D. Duma, J. B. Collins, J. W. Chou, J. A. Cidlowski, Sexually Dimorphic Actions of Glucocorticoids Provide a Link to Inflammatory Diseases with Gender Differences in Prevalence. Sci. Signal. 3, ra74 (2010).

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