Submitted September 6, 2006
Accepted January 31, 2007
Involvement of mast cells in IL-12/23 p40 production is essential for survival from polymicrobial infections
Nobuhiro Nakano, Chiharu Nishiyama*, Shunsuke Kanada, Yusuke Niwa, Naomi Shimokawa, Hiroko Ushio, Makoto Nishiyama, Ko Okumura, and Hideoki Ogawa
Atopy (Allergy) Research Center, Juntendo University School of Medicine, Tokyo, Japan
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan
Department of Dermatology, Juntendo University School of Medicine, Tokyo, Japan
Biotechnology Research Center, The University of Tokyo, Tokyo, Japan
* Corresponding author; email: chinishi{at}med.juntendo.ac.jp.
Interleukin (IL)-12, a heterodimeric cytokine (p35/p40) mainly produced 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-
/lipopolysaccharide (LPS). IL-12 was secreted from BMMCs in response to LPS but not by Fc
RI cross-linking. The p40 levels in 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) BMMCs-reconstituted W/Wv in the acute septic peritonitis model. The survival rate of W/Wv reconstituted with p40-/- BMMCs was significantly decreased lower than those of WBB6F1+/+ and WT-BMMC-reconstituted W/Wv, which was due to reduced production of IFN- and subsequent impaired activation of neutrophils in 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.
