Abstract
Human milk is a source of bioactive substances regulating the development and activity of the newborn immune system. Human milk has been found to contain a number of cytokines, including interleukins, growth factors, and colony stimulating factors. In the present study, we assessed 10 specimens of human milk for the presence of macrophage migration inhibitory factor (MIF), a cytokine recently described in several human reproductive organs and tissues. Using biochemical as well as immunologic techniques, we showed that MIF is abundantly present in human milk, mostly distributed in the lipid layer and in the aqueous phase. Fractionation of the lipid layer showed that MIF is highly concentrated inside milk fat globules. In view of its proinflammatory features, we speculate that milk MIF may protect the newborn against infection and play a role in preserving the functionality of the lactating mammary gland. Furthermore, the localization of MIF in lipid globules suggests a possible strategy for the protection of milk cytokines from the gastric barrier.
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Abbreviations
- MIF:
-
macrophage migration inhibitory factor
- MFG:
-
milk fat globules
- MFGM:
-
milk fat globule membranes
- TBS:
-
Tris-buffered saline
References
Goldman AS 1993 The immune system of human milk: antimicrobial, anti-inflammatory and immunomodulating properties. Pediatr Infect Dis J 12: 664–672
Garofalo RP, Goldman AS 1998 Cytokines, chemokines, and colony-stimulating factors in human milk: the 1997 update. Biol Neonate 74: 134–142
Rudloff HE, Schmalstieg FC, Mushtaha AA, Kimberly H, Palkowetz KH, Liu SK, Goldman AS 1992 Tumor necrosis factor-α in human milk. Pediatr Res 31: 29–33
Munoz C, Endres S, van der Meer J, Schlesinger L, Arevalo M, Dinarello C 1990 Interleukin-1β in human colostrum. Res Immunol 141: 503–513
Bocci V, Von Bremen K, Corradeschi F, Franchi F, Luzzi E, Paulesu L 1993 Presence of interferon-γ and interleukin-6 in colostrum of normal women. Lymphokine Cytokine Res 12: 21–24
Bryan D-L, Hawkes JS, Gibson RA 1999 Interleukin-12 in human milk. Pediatr Res 45: 858–859
Srivastava MD, Srivastava A, Brouhard B, Saneto R, Groh-Wargo S, Kubit J 1996 Cytokines in human milk. Res Commun Mol Pathol Pharmacol 93: 263–287
Garofalo R, Chheda S, Mei F, Palkowetz KH, Rudloff HE, Schmalstieg FC, Rassin DK, Goldman AS 1995 Interleukin-10 in human milk. Pediatr Res 37: 444–449
Gasparoni A, Chirico G, De Amici M, Ravagni-Probizer MF, Ciardelli L, Marchesi ME, Rondini G 1996 Granulocyte-macrophage colony-stimulating factor in human milk. [letter]. Eur J Pediatr 155: 69
Hara T, Irie K, Saito S, Ichijo M, Yamada M, Yanai N, Miyazaki S 1995 Identification of macrophage colony-stimulating factor in human milk and mammary gland epithelial cells. Pediatr Res 37: 437–443
Calhoun DA, LunØe M, Du Y, Christensen RD 2000 Granulocyte colony-stimulating factor is present in human milk and its receptor is present in human fetal intestine. Pediatrics 105: 392–397
Bloom BR, Bennett B 1966 Mechanism of reaction in vitro associated with delayed-type hypersensitivity. Science 153: 80–82
Calandra T, Bernhagen J, Mitchell RA, Bucala R 1994 The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor. J Exp Med 179: 1895–1902
Bernhagen J, Calandra T, Mitchell RA, Martin SB, Tracey KJ, Voelter W, Manogue KR, Cerami A, Bucala R 1993 MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature 365: 756–759
Calandra T, Bernhagen J, Metz CN, Spiegel LA, Bacher M, Donnelly T, Cerami A, Bucala R 1995 MIF as a glucocorticoid-induced modulator of cytokine production. Nature 377: 68–71
Wistow GJ, Shaughnessy MP, Lee DC, Hodin J, Zelanka PS 1993 A macrophage migration inhibitory factor is expressed in the differentiating cells of the eye lens. Proc Natl Acad Sci USA 90: 1272–1275
Matsuda A, Tagawa Y, Matsuda H, Nishihira J 1996 Identification and immunological localization of macrophage migration inhibitory factor in human cornea. FEBS Lett 385: 225–228
Shimizu H, Ohkawara A, Nishihira J, Sakamoto W 1996 Identification of macrophage migration inhibitory factor (MIF) in human skin and its immunohistochemical localization. FEBS Lett 381: 199–202
Imamura K, Nishihira J, Suzuki M, Yasuda K, Sasaki S, Kusunoki Y, Tochimaru H, Takekoshi Y 1996 Identification and immunohistochemical localization of macrophage migration inhibitory factor in human kidney. Biochem Mol Biol Int 40: 1233–1242
Magi B, Bini L, Liberatori S, Marzocchi B, Raggiaschi R, Arcuri F, Tripodi SA, Cintorino M, Tosi P, Pallini V 1998 Charge heterogeneity of macrophage migration inhibitory factor (MIF) in human liver and breast tissue. Electrophoresis 19: 2010–2013
Arcuri F, Cintorino M, Vatti R, Carducci A, Liberatori S, Paulesu L 1999 Expression of macrophage migration inhibitory factor transcript and protein by first trimester human trophoblasts. Biol Reprod 60: 1299–1303
Arcuri F, Ricci C, Ietta F, Cintorino M, Tripodi S, Cetin I, Garzia E, Shatz F, Klemi P, Santopietro R, Paulesu L 2001 Macrophage migration inhibitory factor in the human endometrium: expression and localization during the menstrual cycle and early pregnancy. Biol Reprod 64: 1200–1205
Nishino T, Bernhagen J, Shiiki H, Calandra T, Dohi K, Bucala R 1995 Localization of macrophage migration inhibitory factor (MIF) to secretory granules within the corticotrophic and thyrotrophic cells of the pituitary gland. Mol Med 1: 781–788
Hirokawa J, Sakaue S, Tagami S, Kawakami Y, Sakai M, Nishi S, Nishihira J 1997 Identification of macrophage migration inhibitory factor in adipose tissue and its induction by tumor necrosis factor-α. Biochem Biophys Res Commun 235: 94–98
Meinhardt A, Bacher M, Wennemuth G, Eickhoff R, Hedger M 2000 Macrophage migration inhibitory factor (MIF) as a paracrine mediator in the interaction of testicular somatic cells. Andrologia 32: 46–48
Arcuri F, Del Vecchio MT, De Santi MM, Lalinga AV, Pallini V, Bini L, Bartolommei S, Parigi S, Cintorino M 1999 Macrophage migration inhibitory factor in the human prostate: identification and immunocytochemical localization. Prostate 39: 159–165
Basch JJ, Greenberg R, Farrell HM 1985 Identification of the milk fat globule membrane proteins. II. Isolation of major proteins from electrophoretic gels and comparison of their amino acid compositions. Biochim Biophys Acta 830: 127–135
Laemmli UK 1970 Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227: 680–685
Bradford MM 1976 A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248–254
Görg A, Postel W, Gunther S 1988 The current state of two-dimensional electrophoresis with immobilized pH gradients. Electrophoresis 9: 531–546
Bjellqvist B, Pasquali C, Ravier F, Sanchez JC, Hochstrasser D 1993 A nonlinear wide-range immobilized pH gradient for two-dimensional electrophoresis and its definition in a relevant pH scale. Electrophoresis 14: 1357–1365
Hochstrasser DF, Harrington MG, Hochstrasser AC, Miller MJ, Merril CR 1988 Methods for increasing the resolution of two-dimensional protein electrophoresis. Anal Biochem 173: 424–435
Towbin H, Staehelin T, Gordon J 1979 Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci USA 76: 4350–4354
Bocci V, Von Bremen K, Corradeschi F, Luzzi E, Paulesu L 1991 What is the role of cytokines in the human colostrum?. J Biol Regul Homeost Agent 5: 121–124
Bocci V 1999 The oropharyngeal delivery of interferons: where are we and where do we need to go?. J Interferon Cytokine Res 19: 859–861
Fleischmann WR, Koren S 1999 Systemic effects of orally administered interferons and interleukin-2. J Interferon Cytokine Res 19: 829–839
Goldman AS, Chheda S, Garofalo R, Schmalstieg FC 1996 Cytokines in human milk: properties and potential effects upon the mammary gland and the neonate. J Mammary Gland Biol Neoplasia 1: 251–258
Juul SE, Zhao Y, Dame JB, Du Y, Hutson AD, Christensen RD 2000 Origin and fate of erythropoietin in human milk. Pediatr Res 48: 660–667
Calhoun DA, LunØe M, Du Y, Staba SL, Christensen RD 1999 Concentrations of granulocyte colony-stimulating factor in human milk after in vitro simulation of digestion. Pediatr Res 46: 767–771
Swope MD, Lolis E 1999 Macrophage migration inhibitory factor: cytokine, hormone, or enzyme?. Rev Physiol Biochem Pharmacol 139: 1–32
Metka K, Nada P 1992 The role of exocytosis in the apocrine secretion of milk lipid globules in mouse mammary gland during lactogenesis. Biol Cell 75: 211–216
Wu CC, Howell KE, Neville MC, Yates JR, McManaman JL 2000 Proteomics reveal a link between the endoplasmic reticulum and lipid secretory mechanisms in mammary epithelial cells. Electrophoresis 21: 3470–3482
Onodera S, Suzuki K, Matsuno T, Kaneda K, Takagi M, Nishihira J 1997 Macrophage migration inhibitory factor induces phagocytosis of foreign particles by macrophages in autocrine and paracrine fashion. Immunology 92: 131–137
Weiser WY, Pozzi LM, David JR 1991 Human recombinant migration inhibitory factor activates human macrophages to kill Leishmania donovani. J Immunol 147: 2006–2011
Michie CA, Tantscher E, Schall T, Rot A 1998 Physiological secretion of chemokines in human breast milk. Eur Cytokine Netw 9: 123–129
Ho PC, Lawton JW 1978 Human colostral cells: phagocytosis and killing of E. coli and C. albicans. J Pediatr 93: 910–915
Dabbs DJ 1993 Mammary ductal foam cells: macrophage immunophenotype. Hum Pathol 24: 977–981
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The authors thank Prof. V. Bocci for his critical review of the manuscript and suggestions.
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Supported by a research grant from the Italian Ministry of Education MURST (Founding for Research of National Institute) and from the University of Siena.
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Magi, B., Ietta, F., Romagnoli, R. et al. Presence of Macrophage Migration Inhibitory Factor in Human Milk: Evidence in the Aqueous Phase and Milk Fat Globules. Pediatr Res 51, 619–624 (2002). https://doi.org/10.1203/00006450-200205000-00013
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DOI: https://doi.org/10.1203/00006450-200205000-00013
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