EFFECT OF RETINOIC ACID AND VITAMIN-D ON THE EXPRESSION OF INTERLEUKIN-1-BETA, TUMOR-NECROSIS-FACTOR-ALPHA AND INTERLEUKIN-6 IN THE HUMAN MONOCYTIC CELL-LINE U937

We have previously described a synergism between the two physiological hormones, retinoic acid (RA) and 1alpha,25-dihydroxyvitamin D3 (VD) i n the induction of U937 cell differentiation towards a more mature sta te. Herein, we investigated the regulation of cytokine production duri ng RA and/or VD treatment of U937 cells. Cell differentiation was foll owed by measurement of their capacity to give oxidative responses, and interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha ) and IL-6 gene and protein expression were determined in RA/VD-treate d cells, activated or not with lipopolysaccharide (LPS). The undiffere ntiated and RA-treated U937 cells were unable to produce monokines eve n when they were stimulated by LPS. VD induced the monokine mRNA expre ssion in U937 cells but failed to induce protein release. However, unl ike RA, it primed the cells to secrete monokines upon endotoxin stimul ation. A large enhancement of the production of the monokines both at mRNA and protein levels was observed in the U937 cells exposed to the combination of RA + VD. Nevertheless, protein release required a furth er step of activation of the RA + VD-primed cells. The co-inducer effe ct of RA and VD was not observed in HL-60 or THP-1 cells and seems to be restricted to U937 cells. These results on cytokine expression supp ort our previous finding that a combination of RA and VD brings the U9 37 cells to a high stage of myeloid differentiation with major charact eristics of monocytes/macrophages.