SYNERGISM OF GLUCOCORTICOIDS WITH GRANULOCYTEMACROPHAGECOLONY STIMULATING FACTOR (GM-CSF) BUT NOT INTERFERON GAMMA (IFN-y) OR INTERLEUKIN-4 (IL-4) ON INDUCTION OF HLA CLASS II EXPRESSION ON HUMAN MONOCYTES Roya Sadeghi, Catherine M. Hawrylowicz,* Yuti Chernajovsky, Marc Feldmann Peripheral blood monocytes from up to 13 normal donors were stimulated with the cytokines interferon y (IFN-y), interleukin 4 (IL-4) and granulocyte macropbage-colony stimulating factor (GM-CSF) in the presence or absence of dexametbasone (Dex), and the effects on HLA class II (HLA-DR, DP and DQ) expression studied. Dex markedly augmented HLA-DR, DP and DQ levels induced by GM-CSF, in all samples tested. Particularly striking were the effects on HLA-DQ expression, since stimulation with a combination of Dex and GM-CSF induced markedly higher levels of HLA-DQ antigen than stimulation with IFN-y. Northern blot analysis of samples treated for 40 hours with Dex and GM-CSF indicated that levels of DRcq DPcx and DQcll mRNA were also increased. In contrast, despite variation between indi- vidual donors, in general Dex weakly inhibited both constitutive and IFN-y- or IL-4-induced HLA-DR expression. Variability in the responsiveness of monocytes purified from individual donors to each cytokine was also observed. GM-CSF was less potent than IFN-y and IL-4, enhancing HLA class II expression in only seven of 13 donors tested, whereas in the presence of Dex all donors responded to GM-CSF. The differential effects of glucocorticoids in vitro suggest that these cytokines induce HLA class II expression by different mechanisms. HLA class II molecules play a critical role in the initiation of the immune response, by binding and presenting peptides derived from foreign antigens to specific T cells. HLA class II antigens are expressed on antigen presenting cells, including blood mono- cytes, tissue macrophages, dendritic cells and B lym- phocytes. Expression is induced on many cell types by a variety of cytokines including interferon y (IFNq), From the Charing Cross Sunley Research Centre, Lurgan Avenue, Hammersmith, London W6 8LW. Correspondence to: Professor Marc Feldmann. *Current address: Department of Immunology, St Mary’s Hospital Medical School. Paddineton. London W2 1PG. Received 20 January 1992: revised and accepted for publication 16 March 1992. 01992 Academic Press Limited 1043-4666192/040287+ll $05.00/O KEY WORDS: GM-CSFIIL-4/IFNqldexamethasone/HLA class II CYTOKINE, Vol. 4, No. 4 (July), 1992: pp 287-297 interleukin 4 (IL-4) and GM-CSF and is modulated by agents such as tumour necrosis factor (TNF-a) and glucocorticoids . 1 The effect of these mediators may be important in inflammatory states, including sites of autoimmune disease, where excessive and aberrant HLA class II expression and increased cytokine pro- duction have consistently been noted.* The cytokine IFN-y is considered to be the most important stimulus for inducing HLA class II expression.3 It is a potent inducer of HLA-DR and DP expression and a weaker stimulus for HLA-DQ, in cultures of human monocytes and other myelomonocytic cell lines, including THPI, HL-60 and U937. Enhancement of HLA-DR and DP expression by IL-4 and GM-CSF has been demonstrated in freshly isolated human mono- cyteqb7 although there are conflicting reports on the capacity of IL-4 to induce HLA-DQ expression.“6 GM-CSF has been reported not to enhance HLA-DQ expression.4 Strong stimuli for HLA-DQ induction 287