Human casein alpha s1 induces proinflammatory cytokine expression in monocytic cells by TLR4 signaling. Issue 5 (22nd March 2016)

• Record Type: Journal Article
• Authors: Vordenbäumen, Stefan; Saenger, Thorsten; Braukmann, Achim; Tahan, Tamara; Bleck, Ellen; Jose, Joachim; Schneider, Matthias
• Is Part Of: Molecular nutrition & food research. Volume 60:Issue 5(2016)
• Page Start: 1079
• Page End: 1089
• Publication Date: 2016-03-22
• Subjects: Breast feeding -- Inflammasome -- Milk protein -- Nursing -- Toll‐like receptor 4; Food -- Biotechnology -- Periodicals; Food -- Microbiology -- Periodicals; Nutrition -- Periodicals; Food -- Toxicology -- Periodicals; Nutrition -- Periodicals; Food Microbiology -- Periodicals; Food Technology -- Periodicals; Molecular Biology -- Periodicals; 664.0705
• DOI: 10.1002/mnfr.201500792
• Languages: English
• ISSNs: 1613-4125

Abstract

Abstract : Human casein alpha S1 (CSN1S1) exerts proinflammatory effects via the Toll‐like receptor 4 (TLR4)‐signaling pathway in a phosphorylation‐dependent manner. CSN1S1 induces no expression of cytokines in cells without the TLR4 receptor. Recombinant CSN1S1 exerts expression of cytokine IL‐1β, IL‐6, and IL‐8 in a concentration‐ and time‐dependent manner. Phosphorylation of recombinant CSN1S1 suppresses proinflammatory effects via TLR4‐signaling. Abstract : Scope: 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. Methods and results: 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. Conclusion: 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.