Anti-inflammatory mechanisms of bioactive milk proteins in the intestine of newborns

Abstract

The human newborn infant is susceptible to gut inflammatory disorders. In particular, growth-restricted infants or infants born prematurely may develop a severe form of intestinal inflammation known as necrotizing enterocolitis (NEC), which has a high mortality. Milk provides a multitude of proteins with anti-inflammatory properties and in this review we gather together some recent significant advances regarding the isolation and proteomic identification of these minor constituents of both human and bovine milk. We introduce the process of inflammation, with a focus on the immature gut, and describe how a multitude of milk proteins act against the inflammatory process according to both in vitro and in vivo studies. We highlight the effects of milk proteins such as caseins, and of whey proteins such as alpha-lactalbumin, beta-lactoglobulin, lactoferrin, osteopontin, immunoglobulins, trefoil factors, lactoperoxidase, superoxide dismutase, platelet-activating factor acetylhydrolase, alkaline phosphatase, and growth factors (TGF-β, IGF-I and IGF-II, EGF, HB-EGF). The effects of milk fat globule proteins, such as TLR-2, TLR-4, sCD14 and MFG-E8/lactadherin, are also discussed. Finally, we indicate how milk proteins could be useful for the prophylaxis and therapy of intestinal inflammation in infants and children.

Keywords: A.A.; ACE; AKT; AP; AT(1)/AT(2); Ag; Alpha S1-Casein; Alpha S2-Casein; Angiotensin receptor; Arg-Gly-Asp; BSA; BTC; BTN; Bad; Bax; Bcl-2; Bcl2 antagonist of cell death; C-C motif chemokine 5; CD14; CD36; CD_antigen platelet glycoprotein 4; CNs; COX-2; CTLs; DSS; EGF; EGF receptor; EGFR; ERK1/2; FABP; FK506 binding protein 5; FKBP5/FKBP51; FcRn; Foxp3; GIT; GLP-2; GMP; Gamma-Casein; HB-EGF; HIF-1α; HO-1; IBD; IC-50; IEC; IEL; IGF; IGF-1R; IL-1 receptor-associated kinase 1 and 4; IPP; IRAK1/IRAK4; Inflammation; IntL; Isoleucine-Proline-Proline; LF; LP; LPS; LPSR; LTC(4); MAPK; MASP; MBL; MCP-1/CCL2; MEK; MFG-E8; MFGM; MMPs; Milk proteins; Mw; MyD88; NEC; NF-κB; NO; Necrotizing enterocolitis; Nutrition; OPN; PAF; PAF-AH; PI-3K; PIP(3); PKA; PLA(2); Phosphoinositide 3-kinase; Preterm infant; RAC-alpha serine/threonine-protein kinase; RAF proto-oncogene serine/threonine-protein kinase; RANTES/CCL5; RAS-like protein; RGD; Raf; Ras; SHC-transforming protein; SHR; SMAD; SOCS3; SOD; SVVYGLR; Serine-Valine-Valine-Tyrosine-Glycine-Leucine-Arginine; Shc; TFF3; TGF-β; TGF-β2; TGF-βR; TIMP-1; TIR-domain-containing adapter-inducing I interferon-β; TLR-4; TNBS; TNF-α; TRIF; VPP; Valine-Proline-Proline; a.a.; alkaline phosphatase; alpha-lactalbumin; amino acid; angiotensin; angiotensin converting enzyme; apoptosis regulator Bax; apoptosis regulator Bcl-2; arachidonic acid; beta-casein; beta-lactoglobulin; betacellulin; bovine serum albumin; butyrophilin; caseins; cyclooxygenase-2; cytotoxic T lymphocytes; dextran-sulphate-sodium; epidermal growth factor; extracellular signal-regulated kinase 1/2; fatty acid-binding protein; forkhead box P3; gastrointestinal tract; glucagon-like peptide 2; glycomacropeptide; half maximal inhibitory concentration; heme oxygenase; heparin-binding epidermal growth factor-like growth factor; hypoxia-inducible factor alpha; iNOS; inducible NO synthase; inflammatory bowel disease; insulin-like growth factor; insulin-like growth factor 1 receptor; intelectin; intestinal epithelial cell; intraepithelial lymphocytes; isoelectric point; kappa-casein; lactoferrin; lactoperoxidase; leukotriene B4; lipopolysaccharide; lipopolysaccharide receptor; macrophage chemo attractant protein-1; major histocompatibility complex class I-related Fc receptor; mannose binding lectin; mannose-binding-lectin-associated serine protease; matrix metalloproteinases; milk fat globule epidermal growth factor 8; milk fat globule membrane; mitogen-activated protein kinase; mitogen-activated/extracellular-signal regulated kinase kinase; molecular weight; mothers against decapentaplegic; myeloid differentiation primary response gene (88); necrotizing enterocolitis; nitric oxide; nuclear factor kappa-light-chain-enhancer of activated B cells; osteopontin; pI; pIgR; phosphatidylinositol 3,4,5-triphosphate; phosphoinositide 3-kinase; phospholipase A2; platelet-activating factor; platelet-activating factor-acetylhydroxylase; polymeric Ig receptor; protein kinase A; sCD14; sIgA; secretory IgA; soluble CD14; soluble cluster of differentiation 14; spontaneously hypertensive rat; superoxide dismutase; suppressor of cytokine signaling 3; tissue inhibitor of metalloproteinases; toll-like receptor-4; transforming growth factor-beta; transforming growth factor-beta receptor; transforming growth factor-like beta2; trefoil factor 3; trinitrobenzenesulphonic acid; tumor necrosis factor-α; α(S1)-CN; α(S2)-CN; α-La; β-CN; β-Lg; γ-CN; κ-CN.