Abstract
Glucocorticoids have been exploited therapeutically for more than six decades through the use of synthetic glucocorticoids as anti-inflammatory agents, and are still used in as many as 50% of patients suffering from inflammatory diseases such as rheumatoid arthritis (RA). Better understanding of the mechanisms of action of glucocorticoids could enable the development of therapies that dissociate the broad-spectrum benefits of glucocorticoids from their adverse metabolic effects. The glucocorticoid-induced leucine zipper protein (GILZ; also known as TSC22 domain family protein 3) is a glucocorticoid-responsive molecule whose interactions with signal transduction pathways, many of which are operative in RA and other inflammatory diseases, suggest that it is a key endogenous regulator of the immune response. The overlap between the observed effects of GILZ on the immune system and those of glucocorticoids strongly suggest GILZ as a critical mediator of the therapeutic effects of glucocorticoids. Observations of the immunomodulatory effects of GILZ in human RA synovial cells, and in an in vivo model of RA, support the hypothesis that GILZ is a key glucocorticoid-induced regulator of inflammation in RA. Moreover, evidence that the effect of GILZ on bone loss might be in contrast to those of glucocorticoids suggests manipulation of GILZ as a potential means of dissociating the beneficial anti-inflammatory effects of glucocorticoids from their negative metabolic repercussions.
Key Points
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Glucocorticoids have been used in the therapy of inflammatory diseases such as rheumatoid arthritis (RA) for more than 60 years
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The glucocorticoid-induced leucine zipper protein (GILZ) binds to and inhibits the important proinflammatory transcription factors nuclear factor κB and activator protein 1, and also exerts an inhibitory effect on other signal transduction pathways
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Current data support a role for GILZ in the suppression of both innate and adaptive immune responses
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GILZ potentially mediates the physiological and therapeutic effects of glucocorticoids
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GILZ is expressed in RA synovial tissues, where it exerts inhibitory effects on cytokine expression, and inhibiting the expression of GILZ results in exacerbation of disease in a mouse model of RA
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GILZ is a pivotal endogenous regulator of inflammation in RA and could represent a potential new therapeutic target
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Acknowledgements
The authors' work was supported by the National Health and Medical Research Council of Australia and Arthritis Australia.
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E. Beaulieu and E. F. Morand contributed equally to researching data for the article, discussion of content, writing and reviewing/editing of the manuscript before submission.
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Beaulieu, E., Morand, E. Role of GILZ in immune regulation, glucocorticoid actions and rheumatoid arthritis. Nat Rev Rheumatol 7, 340–348 (2011). https://doi.org/10.1038/nrrheum.2011.59
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DOI: https://doi.org/10.1038/nrrheum.2011.59
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