Transforming growth factor-beta up-regulates CD40-engaged IL-12 productionof mouse Langerhans cells

Transforming growth factor (TGF)-beta is an immunosuppressive agent that is efficacious in suppressing a wide variety of cell-mediated immune response s. However, the direct effect of this cytokine on Langerhans cells (LC) has not been clarified. In this study, we examined its modulatory effects on t he expression of co-stimulatory molecules and LC IL-12 production. A highly purified population of LC (>95%) was prepared from BALB/c mouse skin by th e panning method using anti-I-A(d) mAb. Semiquantitative reverse transcript ion-PCR analysis showed that LC express TGF-beta receptor II mRNA. Interest ingly, TGF-beta (1) enhanced IL-12 p40 production of anti-CD40/IFN-gamma -s timulated LC, despite its down-regulatory effect on CD40 expression. A bioa ssay using an IL-12-dependent T cell line demonstrated the correlation of t he IL-12 p40 level with the bioactivity of IL-12. More importantly, it was found that in contrast to TGF-beta, granulocyte/macrophage colony-stimulati ng factor (GM-CSF) strikingly inhibits IL-12 production of anti-CD40/IFN-ga mma -stimulated LC and that the level of LC IL-12 production is determined by the relative amounts of TGF-beta (1) and GM-CSF. Taken together, these r esults suggest that the two cytokines produced in the skin microenvironment , namely TGF-beta and GM-CSF, exert their important effects on LC function by regulating the secretion of IL-12, a cytokine influencing the Th1-Th2 ba lance.