The Latent Form of Transforming Growth Factor-β Administered Orally Is Activated by Gastric Acid in Mice
The Latent Form of Transforming Growth Factor-β Administered Orally Is Activated by Gastric Acid in Mice
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DOI：
10.3945/jn.109.108761
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发表时间：
2009-08-01
影响因子：
4.2
通讯作者：
Nakao, Atsuhito
中科院分区：
文献类型：
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作者：
Nakamura, Yuki;Miyata, Masanori;Nakao, Atsuhito
转化生长因子-β（TGF β）以潜伏形式丰富于哺乳动物乳汁中。然而，人乳中TGF β的潜伏形式是否在体内转化为活性形式仍然不确定。为了解决这个问题，我们首先研究了是否潜伏性TGF β或人乳汁传播的潜伏性TGF β在体外试验中被激活，模拟胃酸的作用。然后，我们通过用H2受体拮抗剂西咪替丁抑制胃酸来测试胃酸是否是激活小鼠口服潜伏性TGF β或人乳汁携带的潜伏性TGF β所必需的。潜伏性TGF β或人乳汁携带的潜伏性TGF β在pH 1.2时增加MFB-F11报告细胞中的Smad应答启动子活性，但在pH 7.0时不增加，无论是否存在胃蛋白酶胃蛋白酶。在口服潜伏性TGF β（5 μ g/小鼠）的小鼠中，小肠中Smad 2和TGF β靶基因mRNA表达（TGF β和Smad 7）的磷酸化增加（P < 0.05），并且这种作用被西咪替丁（100 mg/kg，腹膜内）抑制。同样，小鼠口服1200 μ L/d含有潜伏性TGF β（3 μ g/L）的人乳2周后，小肠中TGF β和Smad 7 mRNA表达增加（P < 0.05），抗酸剂治疗可抑制这种表达。因此，TGF β的潜伏形式，如人乳中的TGF β，在小鼠中口服给药后可被胃酸激活。该过程可能涉及人乳携带的潜伏TGF β在体内转化为活性形式。J.营养139：1463-1468，2009.
Transforming growth factor-beta (TGF beta) is abundant in mammalian milk in a latent form. However, whether the latent form of TGF beta in human milk is converted to the active form in vivo remains uncertain. To address this issue, we first investigated whether latent TGF beta or human milk-borne latent TGF beta was activated in an in vitro assay, simulating the effects of gastric acid. We then tested whether gastric acid was necessary for the activation of orally administered latent TGF beta or human milk-borne latent TGF beta in mice by inhibiting gastric acidity with cimetidine, an antagonist of H2-receptors. Latent TGF beta or human milk-borne latent TGF beta increased Smad-responsive promoter activity in MFB-F11 reporter cells at pH 1.2, but not at pH 7.0, regardless of the presence or absence of the gastric protease pepsin. In mice treated orally with latent TGF beta (5 mu g/mouse), the phosphorylation of Smad2 and TGF beta target gene mRNA expression (TGF beta and Smad7) was increased in the small intestine (P < 0.05) and this effect was inhibited by cimetidine (100 mg/kg, intraperitoneally). Similarly, mice treated orally with 1200 mu L/d of human milk containing latent TGF beta (3 mu g/L) for 2 wk had increased TGF beta and Smad7 mRNA expression in the small intestine (P < 0.05) and this was inhibited by the antiacid treatment. Therefore, the latent form of TGF beta, such as TGF beta in human milk, can be activated by gastric acid following oral administration in mice, This process may be involved in the conversion of human milk-borne latent TGF beta to the active form in vivo. J. Nutr. 139: 1463-1468, 2009.