Transforming growth factor-beta up-regulates CD40-engaged IL-12 production of mouse Langerhans cells.

Transforming growth factor (TGF)-beta is an immunosuppressive agent that is efficacious in suppressing a wide variety of cell-mediated immune responses. However, the direct effect of this cytokine on Langerhans cells (LC) has not been clarified. In this study, we examined its modulatory effects on the 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 the panning method using anti-I-Ad mAb. Semiquantitative reverse transcription-PCR analysis showed that LC express TGF-beta receptor II mRNA. Interestingly, TGF-beta1 enhanced IL-12 p40 production of anti-CD40/IFN-gamma-stimulated LC, despite its down-regulatory effect on CD40 expression. A bioassay using an IL-12-dependent T cell line demonstrated the correlation of the IL-12 p40 level with the bioactivity of IL-12. More importantly, it was found that in contrast to TGF-beta, granulocyte/macrophage colony-stimulating factor (GM-CSF) strikingly inhibits IL-12 production of anti-CD40/IFN--stimulated LC and that the level of LC IL-12 production is determined by the relative amounts of TGF-beta1 and GM-CSF. Taken together, these results 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 balance.