Cytokine production by mouse myeloid dendritic cells in relation to differentiation and terminal maturation induced by lipopolysaccharide or CD40 ligation

Although it is known that dendritic cells (DCs) produce cytokines, there is little Information about how cytokine synthesis is regulated during DC dev elopment. A range of cytokine mRNA/proteins was analyzed in Immature (CD86( -)) or mature (CD86(+)) murine bone marrow (BM)derived DCs. Highly purified , flow-sorted, immature DCs exhibited higher amounts of interleukin-1 alpha (IL-1 alpha), IL-1 beta, tumor necrosis factor-alpha (TNF-alpha), transfor ming growth factor beta1 (TGF-beta1), and macrophage migration inhibitory f actor (MIF) mRNA/protein than mature DCs. After differentiation, DC up-regu lated the levels of IL-6 and IL-15 mRNA/protein and synthesized de novo, mR NA/protein for IL-12p35, IL-12p40, and IL-18. Although immature BM-derived DCs did not stimulate naive allogeneic T cells, mature DCs elicited a mixed population of T helper (Th) 1 (mainly) and Th2 cells in 3d-mixed leukocyte reactions. CD86+ BM DCs switched to different cytokine patterns according to whether they were terminally differentiated by lipopolysaccharide (LIPS) or CD40 ligation. Although both stimuli increased IL-6, IL-12p40, IL-15, a nd TNF-alpha mRNA/protein levels, only LPS up-regulated transcription of IL -1 alpha, IL-1 beta, IL-12p35, and MIF genes. Although LPS and CD40 crossli nking increased the T-cell allostimulatory function of BM DCs, only LIPS st imulation shifted the balance of naive Th differentiation to Th1 cells, a m echanism dependent on the up-regulation of IL-12p35 and not of IL-23. These results demonstrate that, depending on the stimuli used to terminally matu re BM DCs, DCs synthesize a different pattern of cytokines and exhibit dist inct Th cell-driving potential. (C) 2001 by The American Society of Hematol ogy.