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• W2464837028 abstract "Kirchner et al1Kirchner B. Pfaffl M.W. Dumpler J. von Mutius E. Ege M.J. microRNA in native and processed cow's milk and its implication for the farm milk effect on asthma.J Allergy Clin Immunol. 2016; 137 (1893-5.e13)Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar recently implicated microRNAs of unprocessed cow's milk in mediating the allergy-preventive effect of farm milk.2Loss G. Apprich S. Waser M. Kneifel W. Genuneit J. Büchele G. et al.The protective effect of farm milk consumption on childhood asthma and atopy: the GABRIELA study.J Allergy Clin Immmunol. 2011; 128: 766-773Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar On the basis of translational evidence, we predicted that the transmission of milk-derived immune-regulatory exosomal microRNAs including microRNA-148a, microRNA-155, microRNA-29b, and microRNA-21 prevent atopy by inducing FoxP3+ regulatory T (Treg)-cell differentiation.3Melnik B.C. John S.M. Schmitz G. Milk: an exosomal microRNA transmitter promoting thymic regulatory T cell maturation preventing the development of atopy.J Tranlat Med. 2014; 12: 43Crossref PubMed Scopus (112) Google Scholar Notably, farm milk intake is associated with higher FOXP3 demethylation and higher Treg-cell numbers.4Lluis A. Depner M. Gaugler B. Saas P. Casaca V.I. Raedler D. et al.Increased regulatory T-cell numbers are associated with farm milk exposure and lower atopic sensitization and asthma in childhood.J Allergy Clin Immunol. 2014; 133: 551-559Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar Stable expression of FoxP3 in Treg cells depends on DNA demethylation at the Treg-cell–specific demethylated region, a conserved CpG-rich region within the FOXP3 locus.5Polansky J.K. Schreiber L. Thelemann C. Ludwig L. Krüger M. Baumgrass R. et al.Methylation matters: binding of Ets-1 to the demethylated Foxp3 gene contributes to the stabilization of Foxp3 expression in regulatory T cells.J Mol Med (Berl). 2010; 88: 1029-1040Crossref PubMed Scopus (158) Google Scholar DNA methylation is mediated by DNA methyltransferases (DNMTs). Both DNMT1 and DNMT3b are associated with the FOXP3 locus in CD4+ cells. DNMT1 deficiency results in highly efficient FoxP3 induction following T-cell receptor stimulation.6Josefowicz S.Z. Wilson C.B. Rudensky A.Y. Cutting edge: TCR stimulation is sufficient for induction of Foxp3 expression in the absence of DNA methyltransferase 1.J Immunol. 2009; 182: 6648-6652Crossref PubMed Scopus (128) Google Scholar Importantly, DNMT1 is a direct target of microRNA-148a,7Pan W. Zhu S. Yuan M. Cui H. Wang L. Luo X. et al.MicroRNA-21 and microRNA-148a contribute to DNA hypomethylation in Lupus CD4+ T cells by directly and indirectly targeting DNA methyltransferase 1.J Immunol. 2010; 184: 6773-6781Crossref PubMed Scopus (466) Google Scholar which is abundant in bovine colostrum, mature cow's milk, and human breast milk.3Melnik B.C. John S.M. Schmitz G. Milk: an exosomal microRNA transmitter promoting thymic regulatory T cell maturation preventing the development of atopy.J Tranlat Med. 2014; 12: 43Crossref PubMed Scopus (112) Google Scholar MicroRNA-148a is highly expressed in bovine milk fat and milk fat globules of human breast milk. Boiling of cow's milk results in substantial loss of microRNA-148a-3p.1Kirchner B. Pfaffl M.W. Dumpler J. von Mutius E. Ege M.J. microRNA in native and processed cow's milk and its implication for the farm milk effect on asthma.J Allergy Clin Immunol. 2016; 137 (1893-5.e13)Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar Remarkably, nucleotide sequences of microRNA-148a-3p of Homo sapiens and Bos taurus are identical. MicroRNA-148a directly downregulates the expression of DNMT1 and DNMT3b,7Pan W. Zhu S. Yuan M. Cui H. Wang L. Luo X. et al.MicroRNA-21 and microRNA-148a contribute to DNA hypomethylation in Lupus CD4+ T cells by directly and indirectly targeting DNA methyltransferase 1.J Immunol. 2010; 184: 6773-6781Crossref PubMed Scopus (466) Google Scholar whereas microRNA-21 indirectly inhibits DNMT1 expression by targeting RASGRP1.7Pan W. Zhu S. Yuan M. Cui H. Wang L. Luo X. et al.MicroRNA-21 and microRNA-148a contribute to DNA hypomethylation in Lupus CD4+ T cells by directly and indirectly targeting DNA methyltransferase 1.J Immunol. 2010; 184: 6773-6781Crossref PubMed Scopus (466) Google Scholar MicroRNA-29b, which dose-dependently increases in human serum after intake of pasteurized cow's milk, targets DNMT3a and DNMT3b. Milk exosomes not only transfer microRNAs but also TGF-β, which plays a pivotal role in FoxP3 expression as well as downregulation of DNMT1, DNMT3a, and DNMT3b expression (Fig 1). Thus, milk transmits crucial microRNAs that may be critical effectors for Treg-cell–specific demethylated region FoxP3 demethylation by targeting DNMTs, thereby stabilizing FoxP3 expression. Milk exosomes are of functional importance for the appropriate development of the infant's immune system via transfer of maternal microRNAs and TGF-β, which are derived directly from mammary gland epithelial cells or extruded from milk fat globules. Boiling of milk may disrupt the protective lipid bilayer of milk exosomes, accelerating microRNA degradation. Furthermore, heat-induced alterations of exosomal membrane proteins may disturb the intestinal uptake of milk exosomes. In accordance with our hypothesis,3Melnik B.C. John S.M. Schmitz G. Milk: an exosomal microRNA transmitter promoting thymic regulatory T cell maturation preventing the development of atopy.J Tranlat Med. 2014; 12: 43Crossref PubMed Scopus (112) Google Scholar it has been demonstrated that incubation of PBMCs with isolated human breast milk exosomes increases the number of FoxP3(+)CD4(+)CD25(+) Treg cells. Furthermore, bovine milk exosomes induce FoxP3 expression and Treg-cell differentiation in murine splenocytes. It is of most critical concern that current infant formula contains only negligible amounts of bioactive microRNAs. In contrast to formula feeding, the presence of maternal milk in β-lactoglobulin–sensitized rat pups exhibits an immune response profile similar to that of unchallenged dam-reared rats but with greater FoxP3 mRNA expression and CD4(+) FoxP3(+) cells. In summary, there is accumulating evidence that milk-derived exosomes via transfer of DNMT-targeting microRNAs and exosomal TGF-β stimulate the expression of FoxP3, the peacekeeper of the immune system. A deeper understanding of milk's immunologic functions in postnatal epigenetic imprinting of FOXP3 will enhance our understanding of the pathogenesis and prevention of atopic diseases and offer new strategies for functional improvements of infant formula. microRNA in native and processed cow's milk and its implication for the farm milk effect on asthmaJournal of Allergy and Clinical ImmunologyVol. 137Issue 6PreviewConsumption of unprocessed milk reduces the risk of asthma and atopic sensitization by 30% to 50%.1 Already in the first year of life, consumption of unprocessed milk protects against respiratory tract infections.2 However, consumption of raw milk is no solution because it bears a risk of potentially life-threatening infections.2 Hence there is a need to identify those components of native cow's milk that carry this asthma- and allergy-protective, as well as anti-infectious, effect. A candidate molecule class with relation to immune functions3 are the microRNAs (miRNAs), which have been described in both cow's milk and human breast milk. Full-Text PDF ReplyJournal of Allergy and Clinical ImmunologyVol. 138Issue 3PreviewThe beneficial farm effect on asthma and allergies has been consistently found across many countries; the underlying mechanisms, however, are largely unknown though they are increasingly being deciphered. The induction of A20 in lung epithelial cells, for example, may explain effects triggered by endotoxin exposure.1 Nevertheless, many other contributing pathways have not yet been verified. The persistence of the farm effect into adulthood2 suggests the involvement of epigenetic mechanisms as already discussed in the context of prenatal exposures. Full-Text PDF" @default.
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• W2464837028 title "Milk: An epigenetic inducer of FoxP3 expression" @default.
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