TGF-β1 Inhibits the Release of Histamine and Tumor Necrosis Factor-α from Mast Cells Through an Autocrine Pathway

Transforming growth factor β1 (TGF-β1) is a member of a gene superfamily involved in the regulation of cell growth and differentiation, tissue repair, fibrosis, and inflammatory responses. Given the role of the mast cell (MC) in inflammation and fibrosis, the effect of TGF-β1 on MC mediator release was studied. In vitro treatment of rat peritoneal MC (PMC) with TGF-β1 (10(-10) M) for 20 h followed by washes inhibited (23%) antigen stimulated histamine release. Similar pretreatment of PMC with TGF-β1 (10(-10) M) inhibited (27%) tumor necrosis factor-α (TNF-α) dependent cytotoxicity and reduced (31%) mRNA levels of TNF-α, but did not inhibit nitric oxide (NO) release. By contrast, the presence of TGF-β1 throughout the cytotoxic assay, but without pretreatment of PMC did not modulate TNF-α release. At least 2 h pretreatment with TGF-β1 was required to inhibit MC TNF-α-dependent cytotoxicity. This inhibitory effect of TGF-β1 was abrogated by antibody to TGF-β1. Interestingly, the treatment of PMC with anti-TGF-β1 antibody alone significantly increased the release of histamine and TNF-α. Furthermore, freshly isolated rat PMC (10(7)) contained 35 +/- 7 pg latent TGF-β1 and 51 +/- 9 pg was spontaneously released within 30 min of culture. However, stimulation of PMC with antigen inhibited the spontaneous release of TGF-β1 by 43%. The duration of pretreatment with TGF-β1 required to inhibit MC TNF-α release was similar to that required for downregulation of MC TNF-α-dependent cytotoxicity by IFN-γ. TGF-β1 and IFN-γ had an additive inhibition on TNF-α release by PMC. This inhibitory effect was abrogated and TNF-α-dependent cytotoxicity was enhanced by the addition of anti-TGF-β1 antibody, but not by anti-IFN-γ. These results suggest MC mediator release is regulated by TGF-β1 in an autocrine manner.