The Latent Form of Transforming Growth Factor-β Administered Orally Is Activated by Gastric Acid in Mice

Transforming growth factor-β (TGFβ) is abundant in mammalian milk in a latent form. However, whether the latent form of TGFβ in human milk is converted to the active form in vivo remains uncertain. To address this issue, we first investigated whether latent TGFβ or human milk-borne latent TGFβ 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 TGFβ or human milk-borne latent TGFβ in mice by inhibiting gastric acidity with cimetidine, an antagonist of H2-receptors. Latent TGFβ or human milk-borne latent TGFβ 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 TGFβ (5 μg/ mouse), the phosphorylation of Smad2 and TGFβ target gene mRNA expression (TGFβ 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 μL/d of human milk containing latent TGFβ (3 μg/L) for 2 wk had increased TGFβ and Smad7 mRNA expression in the small intestine (P < 0.05) and this was inhibited by the antiacid treatment. Therefore, the latent form of TGFβ, such as TGFβ 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 TGFβ to the active form in vivo.