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Accumulating evidence suggests that orally ingested lactoferrin protects against inflammation. To assess the efficacy of orally administered bovine lactoferrin (bLF) against hepatitis and to identify the underlying mechanism, in the present study, we used four mouse models of hepatitis induced by d-galactosamine (GalN), carbon tetrachloride (CCl4), GalN plus lipopolysaccharide (LPS) and zymosan plus LPS. Intraperitoneal (i.p.) injection of GalN (500 mg/kg body weight) in mice treated with bovine serum albumin (BSA) for 14 d significantly increased serum aspartate aminotransferase (AST) concentrations compared with the untreated mice. However, orally administered bLF reduced AST concentrations compared with BSA treatment. In mice that received a single injection (0·4 ml/kg) and twice-weekly injections (0·08 ml/kg) of CCl4 for 24 weeks and pretreated with bLF for 14 d and 24 weeks, respectively, significantly suppressed alanine aminotransferase and AST concentrations were observed compared with the BSA-treated control. Oral administration of bLF for 14 d before i.p. injection of LPS (5 mg/kg) plus GalN (1 g/kg) significantly improved the survival rate. In mice that received intravenous injection of zymosan (25 mg/kg) and LPS (15 μg/kg) at 7 d intervals, bLF reduced the elevation of AST concentrations and enhanced the production of IL-11 and bone morphogenetic protein 2 in the small intestine compared with the BSA-treated control. To evaluate the effects of IL-11, we used IL-11 receptor α-null mice treated with GalN, CCl4 and zymosan plus LPS. In this group, the activity of bLF was not significantly different from that of BSA. These data indicate that orally ingested bLF enhances the expression of IL-11 in the small intestine and up-regulates protective activity in mice with hepatitis.

Purpose: Orally administered bovine lactoferrin (bLF) exerts an anti-inflammatory effect on hepatitis and colitis animal models. To investigate the mechanism underlying the action of bLF, we explored the expression of inflammation-related factors in the intestine of a hepatitis mouse model after the oral administration of bLF and in several human intestinal cell lines treated with bLF., Methods: The effects of bLF on the expression of interleukin-11 (IL-11) and bone morphogenetic protein 2 (BMP2) in the intestinal mucosa of a hepatitis mouse model as well as in cell cultures of human intestinal epithelial cells, myofibroblasts, and monocytes were examined using the real-time reverse transcription polymerase chain reaction. Epithelial cells and myofibroblasts were also cocultured using transwells. bLF transport, and IL-11 and BMP2 induction, as well as the interactions between the two cell types, were then analyzed after bLF treatment., Results: In vivo, oral bLF administration increased the production of IL-11 and BMP2 in intestinal specimens. In vitro, bLF only stimulated the production of IL-11 in human intestinal myofibroblasts; i.e., it had no effect on BMP2 production in any cell type. In the transwell cocultures, bLF passed through the epithelium and directly stimulated IL-11 production in the myofibroblasts on the basolateral side. The IL-11 produced in the myofibroblasts subsequently acted protectively on the epithelial cells of the coculture., Conclusions: bLF upregulated the activity of anti-inflammatory factors, such as IL-11, in the intestine of a hepatitis mouse model and human intestinal myofibroblasts.