Involvement of mast cells in IL-12/23 p40 production is essential for survival from polymicrobial infections

Interleukin-12 (IL-12), a heterodimeric cytokine (p35/p40) produced mainly from macrophages and dendritic cells, is an important regulator of T-helper 1 cell responses and for host defense. We found that interferon (IFN) consensus sequence binding protein (ICSBP), which is a transcription factor essential for the expression of p40, was expressed in mouse bone marrow-derived mast cells (BMMCs). The transcription levels of p35 and p40 were increased by stimulation of BMMCs with IFN-gamma/lipopolysaccharide (LPS). IL-12 was secreted from BMMCs in response to LPS but not by FcepsilonRI cross-linking. The p40 levels in the peritoneal cavity of mast cell-deficient W/W(v) and W/W(v) reconstituted with p40(-/-) BMMCs were significantly lower than those of WBB6F(1)(+/+) and wild-type (WT) BMMC-reconstituted W/W(v) in the acute septic peritonitis model. The survival rate of W/W(v) reconstituted with p40(-/-) BMMCs was significantly decreased compared to those of WBB6F(1)(+/+) and WT-BMMC-reconstituted W/W(v), which was due to reduced production of IFN-gamma and subsequent impaired activation of neutrophils in the peritoneal cavity. Survival rate of p40(-/-) mice was also restored by adoptive transfer of WT-BMMCs. These results demonstrate that mast cells play a significant role in the production of IL-12 required for host defense. This is the first report to demonstrate that mast cells are a crucial source of functional IL-12.