Retinoids synergize with interleukin-2 to augment IFN-gamma and interleukin-12 production by human peripheral blood mononuclear cells

We have demonstrated previously that cells from both the skin and periphera l blood from patients with cutaneous T cell lymphoma (CTCL) have elevated l evels of protein and mRNA for Th2 cytokines, interleukin-4 (IL-4) and IL-5, and depressed levels of Th1 cytokines, IL-2 and interferon-gamma (IFN-gamm a), Furthermore, IL-12 in vitro can restore IFN-gamma production by these p atients' cells tot near normal levels, Because retinoids exert therapeutic activity in CTCL and are potent modulators of growth and differentiation of hematopoietic cells, we investigated the role of retinoids in modulating T h1 cytokine production. Peripheral blood mononuclear cells (PBMC) from norm al donors and patients with CTCL were cultured with medium, IL-2, 13-cis-re tinoic acid, all-trans-retinoic acid, acetretin or etretinate alone, or IL- 2 plus the retinoids for 24 h, and levels of IFN-gamma. were determined usi ng ELISA, IL-2 or retinoids alone could induce low but significant levels o f IFN-gamma, However, when IL-2 was cultured with each retinoid, a synergis tic augmentation of IFN-gamma levels (4-fold to 90-fold) was observed excep t in the case of etretinate, All-trans-retinoic acid (ATRA) was the most po tent IFN-gamma inducer. Similar studies performed using PBMC from CTCL pati ents indicated the IFN-gamma augmentation occurred but in a blunted manner. The IFN-gamma-inducing effect of ATRA and 13-cis-retinoic acid could be ab rogated by addition of anti-IL-12 antibodies, suggesting that IL-12 plays a role in the synergistic upregulation of IFN-gamma, Using an IL-12 p40-spec ific radioimmunoassay (RIA), we confirmed the presence of IL-12 in IL-2 plu s retinoid-treated culture supernatants. Purified monocytes cultured with I L-2 plus ATRA did not secrete IL-12. Only when monocytes were cocultured wi th lymphocytes was there an increase in IL-12 production, suggesting the in volvement of a paracrine feedback loop requiring both monocytes and lymphoc ytes. These data suggest that retinoids can induce Th1 cytokines from norma l and CTCL PBMC and that this induction may be mediated through IL-12 produ ction.