Stat4 suppresses the proliferation of connective tissue-type mast cells

Mast cells are the progeny of hematopoietic stem cells, and murine mast cells are usually divided into two distinct populations, mucosal mast cells (MMCs) and connective tissue-type mast cells (CTMCs). We previously reported that CTMCs expressed signal transducer and activator of transcription (Stat) 4, but MMCs did not. Stat4 is also expressed in T cells and plays important roles in their homeostasis. In the present study, we show that Stat4 is involved in the homeostasis of CTMCs. The number of skin CTMCs increased in Stat4-deficient Balb/c mice, but that of gastric MMCs did not, when compared to those in control Balb/c +/+ mice. The comparison between cultured Stat4-deficient CTMCs and cultured Balb/c +/+ CTMCs revealed that cell cycle progression and cyclin D3 expression in the cultured Stat4-deficient CTMCs were enhanced in a Stat3 activation-dependent manner. This phenotype was explained by upregulation of KitL-induced interleukin (IL)-6 acting in an autocrine manner in cultured Stat4-deficient CTMCs. These results show that Stat4 suppresses the proliferation of CTMCs by controlling IL-6 via an autocrine mechanism. Laboratory Investigation (2008) 88:856-864 doi:10-1038/labinvest 2008-51: published online 2 June 2008.