Bissonnette E Y, Enciso J A, Befus A D
Department of Medicine, University of Alberta, Edmonton, Canada.
Am J Respir Cell Mol Biol. 1997 Mar;16(3):275-82. doi: 10.1165/ajrcmb.16.3.9070612.
Transforming growth factor beta1 (TGF-beta1) 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-beta1 on MC mediator release was studied. In vitro treatment of rat peritoneal MC (PMC) with TGF-beta1 (10(-10) M) for 20 h followed by washes inhibited (23%) antigen stimulated histamine release. Similar pretreatment of PMC with TGF-beta1 (10(-10) M) inhibited (27%) tumor necrosis factor-alpha (TNF-alpha) dependent cytotoxicity and reduced (31%) mRNA levels of TNF-alpha, but did not inhibit nitric oxide (NO) release. By contrast, the presence of TGF-beta1 throughout the cytotoxic assay, but without pretreatment of PMC did not modulate TNF-alpha release. At least 2 h pretreatment with TGF-beta1 was required to inhibit MC TNF-alpha-dependent cytotoxicity. This inhibitory effect of TGF-beta1 was abrogated by antibody to TGF-beta1. Interestingly, the treatment of PMC with anti-TGF-beta1 antibody alone significantly increased the release of histamine and TNF-alpha. Furthermore, freshly isolated rat PMC (10(7)) contained 35 +/- 7 pg latent TGF-beta1 and 51 +/- 9 pg was spontaneously released within 30 min of culture. However, stimulation of PMC with antigen inhibited the spontaneous release of TGF-beta1 by 43%. The duration of pretreatment with TGF-beta1 required to inhibit MC TNF-alpha release was similar to that required for downregulation of MC TNF-alpha-dependent cytotoxicity by IFN-gamma. TGF-beta1 and IFN-gamma had an additive inhibition on TNF-alpha release by PMC. This inhibitory effect was abrogated and TNF-alpha-dependent cytotoxicity was enhanced by the addition of anti-TGF-beta1 antibody, but not by anti-IFN-gamma. These results suggest MC mediator release is regulated by TGF-beta1 in an autocrine manner.
转化生长因子β1（TGF-β1）是一个基因超家族的成员，参与细胞生长和分化、组织修复、纤维化及炎症反应的调控。鉴于肥大细胞（MC）在炎症和纤维化中的作用，研究了TGF-β1对MC介质释放的影响。用TGF-β1（10⁻¹⁰ M）体外处理大鼠腹膜MC（PMC）20小时后洗涤，可抑制（23%）抗原刺激的组胺释放。用TGF-β1（10⁻¹⁰ M）对PMC进行类似的预处理可抑制（27%）肿瘤坏死因子-α（TNF-α）依赖性细胞毒性，并降低（31%）TNF-α的mRNA水平，但不抑制一氧化氮（NO）释放。相比之下，在细胞毒性试验全程存在TGF-β1，但未对PMC进行预处理，并未调节TNF-α释放。至少需要用TGF-β1预处理2小时才能抑制MC TNF-α依赖性细胞毒性。TGF-β1的这种抑制作用可被抗TGF-β1抗体消除。有趣的是，单独用抗TGF-β1抗体处理PMC可显著增加组胺和TNF-α的释放。此外，新鲜分离的大鼠PMC（10⁷）含有35±7 pg的潜伏TGF-β1，培养30分钟内可自发释放51±9 pg。然而，用抗原刺激PMC可使TGF-β1的自发释放抑制43%。抑制MC TNF-α释放所需的TGF-β1预处理持续时间与IFN-γ下调MC TNF-α依赖性细胞毒性所需的时间相似。TGF-β1和IFN-γ对PMC释放TNF-α具有相加抑制作用。加入抗TGF-β1抗体可消除这种抑制作用并增强TNF-α依赖性细胞毒性，但加入抗IFN-γ则无此作用。这些结果表明，MC介质释放受TGF-β1以自分泌方式调控。
