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Blood, 1 September 2001, Vol. 98, No. 5, pp. 1512-1523

IMMUNOBIOLOGY

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

Adrian E. Morelli, Alan F. Zahorchak, Adriana T. Larregina, Bridget L. Colvin, Alison J. Logar, Takuya Takayama, Louis D. Falo, and Angus W. Thomson

From the Thomas E. Starzl Transplantation Institute and the Departments of Surgery, Molecular Genetics and Biochemistry, and Dermatology, and the University of Pittsburgh Cancer Institute, University of Pittsburgh Medical Center, PA.

Although it is known that dendritic cells (DCs) produce cytokines, there is little information about how cytokine synthesis is regulated during DC development. 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-1alpha (IL-1alpha ), IL-1beta , tumor necrosis factor-alpha (TNF-alpha ), transforming growth factor beta 1 (TGF-beta 1), and macrophage migration inhibitory factor (MIF) mRNA/protein than mature DCs. After differentiation, DC up-regulated the levels of IL-6 and IL-15 mRNA/protein and synthesized de novo mRNA/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 (LPS) or CD40 ligation. Although both stimuli increased IL-6, IL-12p40, IL-15, and TNF-alpha mRNA/protein levels, only LPS up-regulated transcription of IL-1alpha , IL-1beta , IL-12p35, and MIF genes. Although LPS and CD40 cross-linking increased the T-cell allostimulatory function of BM DCs, only LPS stimulation shifted the balance of naive Th differentiation to Th1 cells, a mechanism dependent on the up-regulation of IL-12p35 and not of IL-23. These results demonstrate that, depending on the stimuli used to terminally mature BM DCs, DCs synthesize a different pattern of cytokines and exhibit distinct Th cell-driving potential.

© 2001 by The American Society of Hematology.
 

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