Interleukin-12 and Flt3 ligand differentially promote dendropoiesis in vivo.
Interleukin-12 (IL-12) and Flt3 ligand (FL) regulate hematopoiesis by stimulating proliferation, differentiation and migration of progenitor and/or stem cells. In this study, we evaluated the in vivo effect of IL-12 alone or in combination with FL on dendritic cell (DC) generation and accumulation in murine spleen, lymph node, thymus, liver, and tumor tissues. Both cytokines induced accumulation of functional DC in lymphoid and non-lymphoid tissues. IL-12 promoted predominantly myeloid dendropoiesis, while FL induced both myeloid and lymphoid dendropoiesis. Combination treatment resulted in a dramatic increase in CD86+, and particularly, NLDC-145+ cells within the liver, which was largely due to cell proliferation. Combination therapy also revealed the ability of FL to protect bone marrow cell populations from IL-12-induced depletion in vivo. In vitro, we found a significant FL-induced up-regulation of IL-12 production by DC at both mRNA and protein levels. Thus, our study suggests that (i) the antitumor activity of IL-12 may, at least in part, be mediated by the stimulation of dendropoiesis and (ii) IL-12 might contribute to the antitumor activity of FL. Furthermore, induction of DC generation in vivo by a combination of IL-12 and FL might become a new approach for immunotherapy of cancer.
Esche
C
C
Biologic Therapy Program, University of Pittsburgh Cancer Institute, PA 15213, USA.
Cai
Q
Q
Peron
J M
JM
Hunter
O
O
Subbotin
V M
VM
Lotze
M T
MT
Shurin
M R
MR
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000502:physiology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013601:T-Lymphocytes / Q000502:physiology
D008565:Membrane Proteins; C084881:flt3 ligand protein; D018664:Interleukin-12