Publication in detail

Arthritis and rheumatism 2013 Jan 17. doi: 10.1002/art.37858. [Epub ahead of print]

Divergent effects of endogenous and exogenous GILZ in models of inflammation and arthritis.

Ngo, D; Beaulieu, E; Gu, R; Leaney, A; Santos, L; Fan, H; Yang, Y; Kao, W; Xu, J; Escriou, V; Loiler, S; Vervoordeldonk, MJ; Morand, EF

Monash University, Clayton, Victoria, Australia.

Objectives: Glucocorticoid-induced leucine zipper (GILZ) has effects on inflammatory pathways that suggest it as a key inhibitory regulator of the immune system, and its expression is exquisitely sensitive to induction by glucocorticoids. We therefore hypothesized that GILZ deficiency would exacerbate models of immune-mediated inflammation, and impair the effects of glucocorticoids on inflammation, and correspondingly that exogenous GILZ would inhibit these events. Methods: Gilz(-/-) mice were generated using the LoxP/Cre system and responses were studied in delayed-type hypersensitivity (DTH), antigen-induced arthritis (AIA), K/BxN serum transfer arthritis, and LPS-induced cytokinemia. Therapeutic expression of GILZ via administration of recombinant adeno-associated virus expressing the Gilz gene was compared to the effects of glucocorticoid in collagen-induced arthritis (CIA). Results: Increased T cell proliferation and DTH were observed in Gilz(-/-) mice but neither AIA or K/BxN arthritis were 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. Conclusion: Despite effects on T cell activation, GILZ deficiency was without impact on effector pathways of arthritis, and was unexpectedly redundant in glucocorticoid effects. These findings do not support GILZ being central to the actions of glucocorticoids, but the efficacy of exogenous GILZ in CIA suggests further evaluation of GILZ in inflammatory disease is required.

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