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

Abstract

AbstractInterleukin-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-γ/lipopolysaccharide (LPS). IL-12 was secreted from BMMCs in response to LPS but not by FcϵRI cross-linking. The p40 levels in the peritoneal cavity of mast cell–deficient W/Wv and W/Wv reconstituted with p40−/− BMMCs were significantly lower than those of WBB6F1+/+ and wild-type (WT) BMMC-reconstituted W/Wv in the acute septic peritonitis model. The survival rate of W/Wv reconstituted with p40−/− BMMCs was significantly decreased compared to those of WBB6F1+/+ and WT-BMMC–reconstituted W/Wv, which was due to reduced production of IFN-γ 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.