The effect of calcineurin inhibitors and corticosteroids on the differentiation of human dendritic cells

Corticosteroids and the calcineurin inhibitors cyclosporin A (CsA) and FK50 6 have been studied extensively regarding their effects on T lymphocytes, b ut their effects on dendritic cells (DC) are relatively unknown. Monocytes are one of the precursors of DC that differentiate into CD14(-)CD1a(+) imma ture DC upon culture with IL-4 and GM-CSF. The presence of CsA or FK506 dur ing differentiation did not affect DC development. In contrast, the presenc e of corticosteroids, either dexamethasone (Dex) or prednisolone (Pred), fo r as little as the first 48 h of culture blocked the generation of immature DC. Dex-DC were unresponsive to signals inducing maturation (CD40 ligand, lipopolysaccharide), as demonstrated by the absence of CD83, CD80/CD86 and HLA-DR up-regulation and their strongly reduced T cell stimulatory capacity . Furthermore, Dex-DC showed a decreased CD40 ligand-induced IL-6 and TNF-a production, a complete block in IL-12p40 production, while IL-10 productio n was unaffected. CsA-DC and FK506-DC showed a partial reduction in the pro duction of TNF-alpha, whereas all other functional activities appeared to b e similar to control DC. These data show that, when compared to calcineurin inhibitors, corticosteroids have a unique and profound inhibitory effect o n the generation and function of DC.