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The Effects of Cytokines on Suppression of Lymphocyte Proliferation by Dexamethasone¹

Tom J. Creed^*,, Richard W. Lee^*, Paul V. Newcomb^*, Alexandra J. di Mambro^*,, Madhuri Raju^* and Colin M. Dayan^2,*

^* Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, United Kingdom; and Department of Gastroenterology, Bristol Royal Infirmary, Bristol, United Kingdom

Treatment failure occurs in up to 30% of patients treated with steroids for inflammatory diseases. The aim of this study was to explore the potential role of 21 cytokines in steroid-resistant inflammatory disease and to develop methods to restore steroid sensitivity through cytokine manipulation. The dexamethasone inhibition of lymphocyte proliferation assay correlates with the outcome of steroid therapy in ulcerative colitis (UC) and other inflammatory diseases. Using this assay, PBMC production of 21 cytokines, assayed by cytokine bead array, was correlated with percentage of suppression of proliferation by 10^–6 M dexamethasone (Imax) in 26 healthy volunteers. Effects of the addition of exogenous cytokines to induce steroid resistance in PBMCs from healthy volunteers and cytokine blockade to improve steroid sensitivity in PBMCs from patients with steroid-resistant UC were then explored. Production of IL-1, IL-10, IL-17, IFN-, G-CSF, GM-CSF, TNF-, and IFN-inducible protein 10 (IP-10) correlated significantly with in vitro steroid sensitivity; however, only IL-2 and TNF- reduced steroid sensitivity when added exogenously. Addition of IL-10 enhanced steroid suppression. Immunoneutralization or receptor blockade of IL-2, but not TNF-, IFN-, IL-4, IL-17, or IP-10 increased steroid sensitivity in cells from steroid-resistant UC patients. Neutralization of IL-10 reduced steroid sensitivity. Of the large panel of cytokines studied, IL-2 appears to have the greatest antagonistic effect on the antiproliferative effect of steroids. These data suggest that IL-2 inhibition in vivo may improve the response to steroids in steroid-resistant individuals.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from Core (Digestive Disorders Foundation) and Novartis Pharmaceuticals.

² Address correspondence and reprint requests to Dr Colin M. Dayan, Dorothy Hodgkin Building, University of Bristol, Whitson Street, Bristol, U.K. BS1 3NY. E-mail address: Colin.dayan{at}bris.ac.uk

³ Abbreviations used in this paper: UC, ulcerative colitis; Imax, maximal percentage suppression of lymphocyte proliferation by dexamthasone (at 10^–6 M dexamethasone); 5-ASA, 5-aminosalicylic acid; GR, glucocorticoid receptor.

⁴ The online version of this article contains supplemental material.