title: The latent form of transforming growth factor-beta administered orally is activated by gastric acid in mice.
abstract: 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.
authors.affiliation: Department of Immunology, Faculty of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Masanori
authors.initials: M
authors.lastname: Miyata
authors.forename: Takashi
authors.initials: T
authors.lastname: Ando
authors.forename: Naomi
authors.initials: N
authors.lastname: Shimokawa
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ohnuma
authors.forename: Ryohei
authors.initials: R
authors.lastname: Katoh
authors.forename: Hideoki
authors.initials: H
authors.lastname: Ogawa
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.forename: Atsuhito
authors.initials: A
authors.lastname: Nakao
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D002927:Cimetidine / Q000494:pharmacology; D005260:Female; D005744:Gastric Acid / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008895:Milk, Human / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism*; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000897:Anti-Ulcer Agents; D012333:RNA, Messenger; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; D002927:Cimetidine