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

Cow milk contains a large amount of an immunoregulatory cytokine, transforming growth factor-beta (TGFbeta). The present study investigated whether commercially available pasteurized cow milk retains TGFbeta activity both in vitro and in vivo. Some commercial cow milk increased TGFbeta/Smad-responsive reporter activity and induced Smad2 phosphorylation and the transcription of the TGFbeta/Smad target genes TGFbeta itself and Smad7 in vitro. Mice treated orally with 500 microL of cow milk containing TGFbeta (3 microg/L) daily for 2 wk had increased phosphorylation of Smad2 and TGFbeta and Smad7 mRNA expression in the intestine. These mice also had significantly greater serum TGFbeta concentrations than the mice treated orally with PBS. Furthermore, oral administration of 500 microL of cow milk containing TGFbeta (3 microg/L) daily for 2 wk before the induction of dextran sodium sulfate colitis and lipopolysaccharide-induced endotoxemia ameliorated tissue damage and mortality, respectively, in mice. These in vivo effects of cow milk were abrogated by the simultaneous administration of TGFbeta type I receptor kinase inhibitor with the cow milk, and they were not observed after the oral administration of cow's milk containing little TGFbeta. In humans, 1 oral challenge of 10 mL/kg cow milk containing TGFbeta (3 microg/L) increased the plasma TGFbeta concentrations at 4 h after the challenge. Thus, some commercially available pasteurized cow milk retains TGFbeta activity, which may be able to provide protection against experimental colitis and endotoxemia associated with increased intestinal and circulating TGFbeta levels.