2008, Number 2
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ABSTRACTMammals produce lactoferrin. It is a nonheme iron binding monomeric glycoprotein considered an essential component of the host innate immune response. The aim of this review was to present the main immunodulatory effects on the after the exposition of heterologous lactoferrin administered by oral or parental routes in experimental animals whether healthy or infected with pathogenic bacteria. Bovine and human lactoferrin enhance or inhibit several humoral and cellular components of immune response involved in prevention or/and resolution of infection and inflammation associated to them. Modulatory effects of heterologous lactoferrin have potential prophylactic, therapeutic, and adjuvant applications. A better understanding of the influence of lactoferrin on immune and inflammatory responses, and its limitations is critically relevant to explore its application on the control of diseases caused by pathogenic bacteria.
Levay PF, Viljoen M. Lactoferrin: A general review. Haematologica. 1995; 80: 252-67.
Ward PP, Uribe-Luna S, Conneely OM. Lactoferrin and host defense. Biochem Cell Biol. 2002; 80: 95-102.
Orsi N. The antimicrobial activity of lactoferrin: current status and perspectives. Biometals. 2004; 17: 189-96.
Vaara M. Agents that increase the permeability of the outer membrane. Microbiol Rev. 1992; 56: 395-411.
Wakabayashi H, Takakura N, Yamauchi K, Tamura Y. Modulation of immunity related gene expression in small intestines of mice by oral administration of lactoferrin. Clin Vaccine Immunol. 2006; 13: 239-45.
Kuhara T, Yamauchi K, Tamura Y, Okamura H. Oral administration of lactoferrin increases NK cell activity in mice via increased production of IL-18 and type I IFN in the small intestine. J Interferon Cytokine Res. 2006; 26: 489-99.
Debbabi H, Dubarry M, Rautureau M, Tome D. Bovine lactoferrin induces both mucosal and systemic responses in mice. J Dairy Res. 1998; 65: 283-93.
Sfeir RM, Dubarry M, Boyaka PN, Rautureau M, Tomé D. The mode of oral bovine lactoferrin administration influences mucosal and systemic immune responses in mice. J Nutr. 2004; 134: 403-9.
Fisher R, Debbabi H, Dubarry M, Boyaka P, Tomé D. Regulation of physiological and pathological Th1 and Th2 responses by lactoferrin. Biochem Cell Biol. 2006; 84: 303-11.
Takakura N, Wakabayashi H, Yamauchi K, Takase M. Influences of orally administered lactoferrin on IFN-g and IL-10 production by intestinal intraepithelial lymphocytes and mesenteric lymph-node cells. Biochem Cell Biol. 2006; 84: 363-8.
Legrand D, Elass E, Carpentier M, Mazurier J. Lactoferrin: a modulator of immune and inflammatory responses. Cell Mol Life Sci. 2005; 62: 2549-59.
Legrand D, Elass E, Carpentier M, Mazurier J. Interactions of lactoferrin with cells involved in immune function. Biochem Cell Biol. 2006; 84: 282-90.
Yamauchi K, Wakabayashi H, Shin K, Takase M. Bovine lactoferrin: benefits and mechanisms of action against infections. Biochem Cell Biol. 2006; 84: 291-6.
Weinberg ED. Human lactoferrin: a novel therapeutic with broad spectrum potential. J Pharm Pharmacol. 2001; 53: 1303-10.
Fisher R, Debbabi H, Blais A, Dubarry M, Rautureau M, Boyaka P, et al. Uptake of ingested bovine lactoferrin and its accumulation in adult mouse tissues. Int Immunopharmacol. 2007; 7: 1387-93.
Damoiseaux J. Regulatory T cells: back to the future. J Med. 2006; 64: 4-9.
Cai G, Kastelein RA, Hunter CA. IL-10 enhances NK cell proliferation, cytotoxicity and production of IFN-gamma when combined with IL-18. Eur J Immunol. 1999; 29: 2658-65.
Tomita M, Wakabayashi H, Yamauchi K, Teraguchi S, Hayasawa H. Bovine lactoferrin and lactoferricin derived from milk: production and applications. Biochem Cell Biol. 2002; 80: 109-12.
Wakabayashi H, Kuwata H, Yamauchi K, Teraguchi S, Tamura Y. No detectable transfer of dietary lactoferrin or its functional fragments to portal blood in healthy adult rats. Biosci Biotechnol Biochem. 2004; 68: 853-60.
Troost F, Steijens J, Saris WHM, Brummer RJM. Gastric digestion of bovine lactoferrin in vivo in adults. J Nutr. 2001; 131: 2101-4.
Takeuchi T, Kitagawa H, Harada E. Evidence of lactoferrin transportation into blood circulation from intestine via lymphatic pathway in adult rats. Exp Physiol. 2004; 89: 263-70.
Kuwata H, Yip TT, Yamauchi K, Teraguchi S, Hayasawa H, Tomita M, et al. The survival of ingested lactoferrin in the gastrointestinal tract of adult mice. Biochem J. 1998; 334(Pt 1): 321-3.
Kuwata H, Yip TT, Tomita M, Hutchens TW. Direct evidence of the generation in human stomach of an antimicrobial peptide domain (lactoferricin) from ingested lactoferrin. Biochim Biophys Acta. 1998; 1429: 129-41.
Troost F, Saris WHM, Brummer RJM. Orally ingested human lactoferrin is digested and secreted in the upper gastrointestinal tract in vivo in women with ileostomies. J Nutr. 2002; 132: 2597-2600.
Gifford JL, Hunter HN, Vogel HJ. Lactoferricin: a lactoferrin derived peptide with antimicrobial, antiviral, antitumor and immunological properties. Cell Mol Life Sci. 2005; 62: 2588-98.
Miyauchi H, Kaino A, Shinoda I, Fukuwatari Y, Hayasawa H. Immunomodulatory effect of bovine lactoferrin pepsin hydrolysate on murine splenocytes and Peyer´s patch cells. J Dairy Sci. 1997; 80: 2330-9.
Kawai T, Akira S. TLR signaling. Cell Death Differ. 2006; 13: 816-25.
Curran CS, Demick KP, Mansfield JM. Lactoferrin activates macrophages via TLR4 dependent and independent signaling pathways. Cell Immunol. 2006; 242: 23-30.
Wrackmeyer U, Hansen GH, Seya T, Danielsen EM. Intelectin: a novel lipid raft associated protein in the enterocytes brush border. Biochemistry. 2006; 45: 9188-97.
Zagulski T, Lipiñski P, Zagulska A, Broniek S, Jarzbek Z. Lactoferrin can protect mice against a lethal dose of Escherichia coli in experimental infection in vivo. Br J Exp Path. 1989; 70: 687-704.
Zagulski T, Lipiñski P, Zagulska A, Jarzbek Z. Antibacterial system generated by lactoferrin in mice in vivo is primarily a killing system. Int J Exp Path. 1998; 79: 117-23.
Zimecki M, Artym J, Chordazek G, Kocieba M, Kruzel ML. Protective effects of lactoferrin in Escherichia coli induced bacteremia in mice: relationship to reduced serum TNF alpha level and increased turnover of neutrophils. Inflamm Res. 2004; 53: 292-6.
Kawasaki Y, Tazume S, Shimizu K, Matsuzawa H, Dosako S, Isoda H, et al. Inhibitory effects of bovine lactoferrin on the adherence of Escherichia coli to host cells. Biosci Biotechnol Biochem. 2000; 64: 348-54.
Edde L, Hipolito RB, Hwang FF, Headon DR, Shalwitz RA, Sherman MP. Lactoferrin protects neonatal rats from gut related systemic infection. Am J Physiol Gastrointest Liver Physiol. 2001; 281: G1140-50.
Håversen LA, Engberg I, Baltzer L, Dolphin G, Hanson LÅ, Mattsby-Baltzer I. Human lactoferrin and peptides derived from a surface exposed helical region reduce experimental Escherichia coli urinary tract infection in mice. Infec Immun. 2000; 68: 5816-23.
Gomez HF, Ochoa TJ, Herrera-Insua I, Carlin LG, Cleary TG. Lactoferrin protects rabbits from Shigella flexneri induced inflammatory enteritis. Infect Immun. 2002; 70: 7050-3.
Dial EJ, Hall LR, Serna H, Romero JJ, Fox JG, Lichtenberger LM. Antibiotic properties of bovine lactoferrin on Helicobater pylori. Dig Dis Sci. 1998; 43: 2750-6.
Wang X, Hirmo S, Willén R, Wadström T. Inhibition of Helicobacter pylori infection by bovine milk glycoconjugates in a BALB/cA mouse model. J Med Microbiol. 2001; 50: 430-5.
Bhimani RS, Vendrov Y, Furmanski P. Influence of lactoferrin feeding and injection against systemic staphylococcal infections in mice. J Appl Microbol. 1999; 86: 135-44.
Lee HY, Park JH, Seok SH, Baek MW, Kim DJ, Lee BH, et al. Potential antimicrobial effects of human lactoferrin against oral infection with Listeria monocytogenes. J Med Microbiol. 2005; 54(Pt 11): 1049-54.
Schaible UE, Collins HL, Priem F, Kaufmann SH. Correction of the iron overload defect in beta-2-microglobulin knockout mice by lactoferrin abolishes their increased susceptibility to tuberculosis. J Exp Med. 2002; 196: 1507-13.
Teraguchi S, Shin K, Ozawa K, Nakamura S, Fukuwatari Y, Tsuyuki S, et al. Bacteriostatic effect of orally administered bovine lactoferrin on proliferation of Clostridium species in the gut of mice fed bovine milk. Appl Environ Microbiol. 1995; 61: 501-6.
Teraguchi S, Shin K, Ogata T, Kingaku M, Kaino A, Miyauchi H, et al. Orally administered bovine lactoferrin inhibits bacterial translocation in mice fed bovine milk. Appl Environ Microbiol. 1995; 61: 4131-4.
Ogata T, Teraguchi S, Shin K, Kingaku M, Fukuwatari Y, Kawase K, et al. The mechanism of in vivo bacteriostasis of bovine lactoferrin. Adv Exp Med Biol. 1998; 443: 239-46.
Teraguchi S, Wakabayashi H, Kuwata H, Yamauchi K, Tamura Y. Protection against infections by oral lactoferrin: Evaluation in animal models. Biometals. 2004; 17: 231-4.
Hwang SA, Kruzel ML, Actor JK. Lactoferrin augments BCG vaccine efficacy to generate T helper response and subsequent protection against challenge with virulent Mycobacterium tuberculosis. Int Immunopharmacol. 2005; 5: 591-9.
Guillén C, McInnes IB, Vaughan DM, Kommajosyula S, Van Berkel PHC, Leung BP, et al. Enhanced Th1 response to Staphylococcus aureus infection in human lactoferrin transgenic mice. J Immunol. 2002; 168: 3950-7.
Kruzel ML, Actor JK, Boldogh I, Zimecki M. Lactoferrin in health and disease. Postepy Hig Med Dosw (on line). 2007; 61: 261-7.
Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol. 2004; 5: 987-95.
Li KJ, Lu MC, Hsieh SC, Wu CH, Yu HS, Tsai CY, et al. Release of surface-expressed lactoferrin from polymorphonuclear neutrophils after contact with CD4+ T cells and its modulation on Th/Th2 cytokine production. J Leukoc Biol. 2006; 80: 350-8.
Wilk KM, Hwang SA, Actor JK. Lactoferrin modulation of antigen presenting cell response to BCG infection. Postepy Hig Med Dosw (online). 2007; 61: 277-82.
Okuda M, Nakazawa T, Yamauchi K, Miyashiro E, Koizumi R, Booka M, et al. Bovine lactoferrin is effective to suppress Helicobacter pylori colonization in the human stomach: a randomized, double-blind, placebo-controlled study. J Infect Chemother. 2005; 11: 265-9.
Guttner Y, Windsor HM, Viiala CH, Marshall BJ. Human recombinant lactoferrin is ineffective in the treatment of human Helicobacter pylori infection. Aliment Pharmacol Ther. 2003; 17: 125-9.
Di Mario F, Aragona G, Dal Bo N, Cavallaro L, Marcon V, Olivieri P, et al. Bovine lactoferrin for Helicobacter pylori eradication: an open, randomized, multicentre study. Aliment Pharmacol Ther. 2006; 23: 1235-40.
Zimecki M, Wlaszczyk A, Cheneau P, Brunel AS, Mazurier J, Spik G, et al. Immunoregulatory effects of a nutritional preparation containing bovine lactoferrin taken orally by health individuals. Arch Immunol Ther Exp. 1998; 46: 231-40.
Zimecki M, Spiegel K, Wlaszczyk A, Kubler A, Kruzel ML. Lactoferrin increases the output of neutrophil precursors and attenuates the spontaneous production of TNF-alpha and IL-6 by peritoneal blood cells. Arch Immunol Ther Exp. 1999; 47: 113-8.
Ishikado A, Imanaka H, Takeuchi T, Harada E, Makino T. Liposomalization of lactoferrin enhanced it´s anti-inflammatory effects via oral administration. Biol Pharm Bull. 2005; 28: 1717-21.
Takeuchi T, Jyonotsuka T, Kamemori N, Kawano G, Shimizu H, Ando K, et al. Enteric formulated lactoferrin was more effectively transported into blood circulation from gastrointestinal tract in adult rats. Exp Physiol. 2006; 91: 1033-40.
Zimecki M, Kruzel ML. Systemic or local co-administration of lactoferrin with sensitizing dose of antigen enhances delayed type hypersensitivity in mice. Immunol Lett. 2000; 74: 183-8.
Chodaczek G, Zimecki M, Lukasiewics J, Lugowski C. A complex of lactoferrin with monophosphoryl lipid A is an efficient adjuvant of the humoral and cellular immune response in mice. Med Microbiol Immunol. 2006; 195: 207-16.
Yamauchi K, Toida T, Nishimura S, Nagano E, Kusuoka O, Teraguchi S, et al. Thirteen week oral repeated administration toxicity study of bovine lactoferrin in rats. Food Chem Toxicol. 2000; 38: 503-12.
Appel MJ, van Veen HA, Vietsch H, Salaheddine M, Nuijens JH, Ziere B, et al. Sub-chronic (13 week) oral toxicity study in rats with recombinant human lactoferrin produced in the milk of transgenic cows. Food Chem Toxicol. 2006; 44: 964-73.
Ling JML, Schryvers AB. Perspectives on interactions between bacteria and lactoferrin. Biochem Cell Biol. 2006; 84: 275-81.
Esaguy N, Aguas AP, van Embden JD, Silva MT. Mycobacteria and human autoimmune disease: direct evidence of cross reactivity between human lactoferrin and the 65 kilodalton protein of tubercle and leprosy bacilli. Infect Immun. 1991; 59: 1117-25.
Kruzel ML, Zimecki M. Lactoferrin and immunological dissonance: clinical implications. Arch Immunol Ther Exp. 2002; 50: 399-410.