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Topical Glucocorticoid Therapy Directly Induces Up-Regulation of Functional CXCR4 on Primed T Lymphocytes in the Aqueous Humor of Patients with Uveitis¹

S. John Curnow^2,*,, Kaska Wloka^2,*,, Jeff M. Faint^*, Nicole Amft^*, C. M. Gemmy Cheung, Vijay Savant, Janet Lord^*, Arne N. Akbar, Christopher D. Buckley^*, Philip I. Murray and Mike Salmon^3,*

^* Department of Rheumatology, Medical Research Council Centre for Immune Regulation, Division of Immunity and Infection, Medical School, University of Birmingham, Birmingham, United Kingdom; Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham, Birmingham and Midland Eye Centre, Sandwell and West Birmingham Hospitals NHS Trust, City Hospital, Birmingham, United Kingdom; Windeyer Institute of Medical Sciences, Royal Free and University College Medical School, London, United Kingdom

Overexpression of the constitutive chemokine receptor CXCR4 has been shown to contribute to the accumulation of leukocytes at sites of chronic inflammation. Glucocorticoids are widely used to treat inflammatory disorders such as uveitis to considerable effect, yet paradoxically have been reported to increase CXCR4 expression in vitro. We show here that ocular lymphocytes isolated from patients with uveitis who had been treated with topical glucocorticoids expressed highly elevated levels of CXCR4. The up-regulation of CXCR4 could be reproduced in vitro by culture of CD4⁺ T cells with aqueous humor (AqH), indicating a role for the ocular microenvironment rather than preferential recruitment of CXCR4⁺ cells. Untreated uveitis and noninflammatory AqH up-regulated CXCR4 to a limited extent; this was dependent on TGF-2. However, the highest levels of CXCR4 both in vivo and in vitro were found in the glucocorticoid-treated patients. Glucocorticoids appeared to be directly responsible for the induction of CXCR4 in treated patients, as the glucocorticoid receptor antagonist RU38486 inhibited the in vitro up-regulation by AqH from these patients. Dexamethasone selectively up-regulated CXCR4 in vitro, but not any of a wide range of other chemokine receptors. CXCL12, the ligand for CXCR4, was present in AqH under noninflammatory conditions, but the levels were low in untreated uveitis and undetectable in treated uveitis AqH. The importance of these results for the treatment of HIV patients with glucocorticoids is discussed as well as a role for glucocorticoid-induced CXCR4 up-regulation and CXCL12 down-regulation in controlling the migration of lymphocyte populations, resulting in resolution of inflammation.

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