title: Human casein alpha s1 induces proinflammatory cytokine expression in monocytic cells by TLR4 signaling.
abstract: Human casein alpha S1 (CSN1S1) is a milk-derived protein, which gives rise to sustained antibody formation after breast feeding in infancy and induces the expression of proinflammatory cytokines. So far, the cellular CSN1S1 receptor is unrecognized. Our objective was to identify the receptor employed by CSN1S1 to induce proinflammatory effects.
  
  
  
  CSN1S1 concentration and time dependently induced expression of IL-1β, IL-8, and IL-6 in monocytic cells despite addition of polymyxin B, which completely abrogated LPS effects. Coincubation of monocytic cells with a neutralizing antibody to Toll-like receptor 4 (TLR4) but not to TLR2 inhibited CSN1S1-induced effects. In TLR4/MD2/CD14-cotransfected HEK293 cells CSN1S1 increased IL-8 expression, while untransfected cells were completely unresponsive. Furthermore, CSN1S1-induced IL1-β secretion was impeded by inhibition of MyD88 and caspase-1. Flow cytometric in vitro assays confirmed binding of CSN1S1 to TLR4. Phosphorylation of CSN1S1 by casein-kinase 2 completely abolished proinflammatory cytokine induction and binding to TLR4.
  
  
  
  CSN1S1 is a multifunctional milk protein that exerts proinflammatory properties via TLR4 and the inflammasome pathway in a phosphorylation-dependent manner. The contribution of CSN1S1 in mother milk to the development of a potent immune system in breastfed individuals should be further assessed.
authors.affiliation: Medical Faculty, Department of Rheumatology and Hiller Research Unit Rheumatology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Vordenbäumen
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, PharmaCampus, Westfälische Wilhelms-University Münster, Münster, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Saenger
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, PharmaCampus, Westfälische Wilhelms-University Münster, Münster, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Braukmann
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, PharmaCampus, Westfälische Wilhelms-University Münster, Münster, Germany.
authors.forename: Tamara
authors.initials: T
authors.lastname: Tahan
authors.affiliation: Medical Faculty, Department of Rheumatology and Hiller Research Unit Rheumatology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Bleck
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, PharmaCampus, Westfälische Wilhelms-University Münster, Münster, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Jose
authors.affiliation: Medical Faculty, Department of Rheumatology and Hiller Research Unit Rheumatology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schneider
mesh_terms: D002364:Caseins / Q000378:metabolism*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D016207:Cytokines / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: C508606:CXCL8 protein, human; D002364:Caseins; D016207:Cytokines; C508585:IL1B protein, human; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D020170:Caspase 1
keywords: Breast feeding; Inflammasome; Milk protein; Nursing; Toll-like receptor 4