Divergent Effects of Endogenous and Exogenous Glucocorticoid-Induced Leucine Zipper in Animal Models of Inflammation and Arthritis
Article first published online: 23 APR 2013
Copyright © 2013 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 65, Issue 5, pages 1203–1212, May 2013
How to Cite
Ngo, D., Beaulieu, E., Gu, R., Leaney, A., Santos, L., Fan, H., Yang, Y., Kao, W., Xu, J., Escriou, V., Loiler, S., Vervoordeldonk, M. J. and Morand, E. F. (2013), Divergent Effects of Endogenous and Exogenous Glucocorticoid-Induced Leucine Zipper in Animal Models of Inflammation and Arthritis. Arthritis & Rheumatism, 65: 1203–1212. doi: 10.1002/art.37858
- Issue published online: 23 APR 2013
- Article first published online: 23 APR 2013
- Accepted manuscript online: 17 JAN 2013 03:39PM EST
- Manuscript Accepted: 3 JAN 2013
- Manuscript Received: 26 MAY 2012
- National Health and Medical Research Council of Australia
Glucocorticoid-induced leucine zipper (GILZ) has effects on inflammatory pathways that suggest it to be a key inhibitory regulator of the immune system, and its expression is exquisitely sensitive to induction by glucocorticoids. We undertook this study to test our hypothesis that GILZ deficiency would exacerbate experimental immune-mediated inflammation and impair the effects of glucocorticoids on inflammation and, correspondingly, that exogenous GILZ would inhibit these events.
GILZ−/− mice were generated using the Cre/loxP system, and responses were studied in delayed-type hypersensitivity (DTH), antigen-induced arthritis (AIA), K/BxN serum–transfer arthritis, and lipopolysaccharide (LPS)–induced cytokinemia. Therapeutic expression of GILZ via administration of recombinant adeno-associated virus expressing the GILZ gene (GILZ-rAAV) was compared to the effects of glucocorticoid in collagen-induced arthritis (CIA).
Increased T cell proliferation and DTH were observed in GILZ−/− mice, but neither AIA nor K/BxN serum–transfer arthritis was affected, and GILZ deficiency did not affect LPS-induced cytokinemia. Deletion of GILZ did not impair the effects of exogenous glucocorticoids on CIA or cytokinemia. In contrast, overexpression of GILZ in joints significantly inhibited CIA, with an effect similar to that of dexamethasone.
Despite effects on T cell activation, GILZ deficiency had no effect on effector pathways of arthritis and was unexpectedly redundant with effects of glucocorticoids. These findings do not support the hypothesis that GILZ is central to the actions of glucocorticoids, but the efficacy of exogenous GILZ in CIA suggests that further evaluation of GILZ in inflammatory disease is required.