Regulation of cytokine and cytokine receptor expression Journal of E.eukocyte Biology Volume 60, November 1996 563 by glucocorticoids Wassim V. Almawi Hayfa N. Beyhum Amal A. Rahme and Michael J. Riedert *Depa,.tmepj of Biochemistry, Faculty of Medicine, American Univet ity of Beirut, Lebanon; and tDepartment of Pharmacology & Toxicology University of Western Ontario, London, Canada Abstract: Glucocorticoids (GCS) profoundly inhibit several aspects of T cell immunity largely through in- hibition of cytokine expression at the transcriptional and posttranscriptional levels. GCS were also reported to act indirectly by inducing transforming growth factor- 13expression, which in turn blocks T cell immunity. hi exerting their antiproliferative effects, GCS diffuse into target cells where they bind their cytoplasmic re- ceptor, which in turn translocates to the nucleus where it inhibits transcription of cytokine genes through di- rect binding to the glucocorticoid response elements (GRE), which are located in the promoter region of cytokine genes or, alternatively, through antagonism of the action of transcription factors required for optimal transcriptional activation. In contrast to their inhibitory effects on cytokine expression, GCS up- regulate cytokine receptor expression that correlates with enhanced cytokine effects on target cells. In this review, we summarize the current state of knowledge of the mechanism of action of GCS, including the phenomenon of steroid-induced rebound, which ensues upon GCS withdrawal. J. Leukoc. Biol. 60: 563-572; 1996. Key Words: interleukins . transcriptionfactors . gene evpression. mRNA . T celLs INTRODUCTION Glucocorticoids (GCS) have been successfully used in the management of several disorders associated with height- ened immunity, such as transplant rejection auto- immune diseases [2, 3J, and inflammatory disorders 4, 51. It remains unknown as to the precise locus of GCS ac- tion because there is evidence of inhibition by GCS of T cell immunity at several stages of T cell activation. The mechanisms postulated for GCS suppression of T cell pro- liferation include the following: (1) induction of the phos- pholipid and calcium-binding proteins, lipocortins, which in turn inhibit arachidonic acid release from membrane- bound stores 161; (2) interference with transmembrane ionic fluxes 171; (3) modulation of activation-induced cell death 18, 91; and (4) inhibition of recruitment of neutro- phils and monocytes-macrophages into inflammatory sites [10, 11J, largely through inhibition of the expression of leukocyte adhesion molecules induced by interferon-? (IFN-y) 1121, tumor necrosis factor-a (TNF-a) 1131, lipo- polysaccharide (LPS) 1141, and interleukin-1 (IL-i) [11J; and (5) suppression ofcytokine production 115-181 and ac- tion 119, 20J. However, it is likely that GCS may exert their effects by a multitude of mechanisms depending on the cell type and activation state. Over the past few years our understanding of the mode of action of GCS and the divergent pathways of T cell ac- tivation, including a molecular and cellular investigation into the biology of T cell-derived cytokines, has provided an opportunity for assessment of the mode of action of the GCS at the molecular level. In this review we present an overview of the current state of knowledge at the cellular and molecular levels pertaining to the mechanism of action of the GCS as immunosuppressive agents. In addition, we shall provide an immunological basis for the GCS-induced rebound phenomenon, which ensues upon acute/short- term GCS withdrawal. T CELL ACTIVATION T cell activation is a tightly regulated process that involves interaction of the multimeric T cell receptor (TcR)/CD3 complex with antigenic fragments expressed on the surface of professional antigen-presenting cells (APC) and other cells [21, 221. Optimal T cell activation also requires the participation of accessory signals imparted by APC, includ- ing interaction of T cell-associated CD2 123-251 and/or CD28/CTLA-4 126, 271 with APC-expressed LFA-3/CD58 and/or B7/BB1, respectively. In addition, co-stimulatory sig- nals imparted in part by APC-derived cytokines, namely IL-i [28-301 and IL-6 131, 321 augment T cell activation, Abbreviations: GCS, glucocorticoids; IFN-’y, interferon-y; TNF-a, tumor necrosis factor-a; LPS, lipopolysaccharide; IL-i, interleukin-1; APC, antigen-presenting cells; PTK, protein tyrosine kinase; PLC, phos- pholipase C; 1P3, inositol 1,4,5-trisphosphate; DAG, diacylglycerol; PKC, protein kinase C; GR, GCS receptor; GM-CSF, granulocyte- macrophage colony-stimulating factor; TGF- 3, transforming growth factor-n; PBMC, peripheral blood mononuclear cells; iNOS, inducible nitric oxide synthase; GRE, glucocorticoid response elements. Correspondence: Dr. Wassim Y. Almawi, Department of Biochem- istry, American University of Beirut, 850 Third Avenue, New York, NY 10022. Received April 15, 1996; revised June 9, 1996; accepted June 14, 1996.