Lactoferrin Induces Concentration-Dependent Functional Modulation of Intestinal Proliferation and Differentiation

Abstract

Human milk stimulates intestinal development through the effects of various moieties. Lactoferrin (LF) is a glycoprotein of human milk whose concentration is highest in colostrum decreasing in mature milk. LF promotes enterocyte growth in intestinal cell lines. We tested the hypothesis that LF induces a distinct effect on enterocyte proliferation and differentiation, depending on its concentration. We examined the dose-related effects by humannative LF (N-LF) in Caco-2 (human colon adenocarcinoma) cells. At high concentrations, N-LF stimulated cell proliferation in immature Caco-2 cells, as judged by 3 H-thymidine incorporation. In contrast, sucrase and lactase activities were increased at low but not high LF concentrations and their mRNA were also increased, indicating a transcriptional effect. Because iron binds specific LF sites, we compared the potency of N-LF and iron-saturated LF (I-LF) and found the native form more potent. Finally, we tested the effects by bovine LF (bLF) in the same system and found the latter more potent than the human isoform in inducing cell growth and lactase expression. These results suggest that LF directly induces enterocyte growth and proliferation, depending on its concentration, thereby regulating the earlyx postnatal intestinal development. bLF could be added to infant formula as a growth factor in selected intestinal diseases.

Polar Effects on Ion Transport and Cell Proliferation Induced by GC-C Ligands in Intestinal Epithelial Cells

“…Its activated form is highly expressed in proliferating enterocytes and is reduced during differentiation (15). In addition, ERK1/2 signaling mediates the intestinal cell proliferation induced by such growth factors as glutamine (21), glucagon-like peptide-2 (22), growth hormone (23), and lactoferrin (24,25).…”

Protective Effects of Lactoferrin against Intestinal Mucosal Damage Induced by Lipopolysaccharide in Human Intestinal Caco-2 Cells

“…18) Lf induces the concentration-dependent functional modulation of intestinal proliferation and diŠerentia-tion. 19) Lf appears to have an important natural mechanism for regulating epithelial cell responses to pathogenic bacteria and in limiting cell damage and the spread of infections. 20) Lf-speciˆc receptors have been identiˆed in the brush-border membrane of fetal and infant intestine, 21) and Lf receptor abundance has been reported to signiˆcantly increase with age.…”

Recombinant Human Intelectin Binds Bovine Lactoferrin and Its Peptides

“…The primary structure of bLF is 69% identical to hLF. 23) In in vitro studies, both hLF and bLF had been shown to induce proliferation and differentiation of human enterocytes 10) and to modulate their cytokine production. 11) In human clinical studies, beneficial effects of orally administered bLF have been demonstrated on lower respiratory tract illness in formula-fed infants, 14) skin infections by fungi in adults, 12) chronic hepatitis C in adults, 13) and on iron metabolism in formula-fed infants 14) and pregnant women.…”

“…3,5) LF, a member of the transferrin family with molecular mass of about 80 kDa, is a component of milk, saliva, tears, airway mucus and secondary granule of neutrophils. 6,7) LF has a wide range of biological functions, including antimicrobial activities against pathogens, 8) immuno-modulatory/ anti-inflammatory effects, 9) regulation of cell proliferation, 10) and intestinal iron absorption. 5) Similar to human LF (hLF), bovine LF (bLF) has been shown to induce proliferation and differentiation of human enterocytes 10) and to modulate their cytokine production.…”

“…6,7) LF has a wide range of biological functions, including antimicrobial activities against pathogens, 8) immuno-modulatory/ anti-inflammatory effects, 9) regulation of cell proliferation, 10) and intestinal iron absorption. 5) Similar to human LF (hLF), bovine LF (bLF) has been shown to induce proliferation and differentiation of human enterocytes 10) and to modulate their cytokine production. 11) Beneficial effects of orally administered bLF on infections and iron status have also been recently demonstrated in clinical trials in human adults and infants.…”