Human casein alpha s1 induces proinflammatory cytokine expression in monocytic cells by TLR4 signaling

Abstract

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.

Ser71 of αS1‐Casein is Phosphorylated in Breast Milk—Evidence from Targeted Mass Analysis

“…The protein is able to induce proinflammatory cytokine expression in monocytic cells by toll‐like receptor 4 (TLR‐4)‐signaling, it leads to in vitro differentiation of monocytes towards macrophages, and it upregulates the production of GM‐CSF via p38 MAP kinase in human monocytes . More recently our group has also shown that the phosphorylation of αS1‐casein by casein kinase (CK) 2 completely abolished binding to TLR‐4 and proinflammatory cytokine induction. Conclusively, we were interested in the concentration of αS1‐casein in breast milk .…”

Site-Specific Labeling of Protein Kinase CK2: Combining Surface Display and Click Chemistry for Drug Discovery Applications

“…Here, the change of thermophoresis of a fluorescent protein induced by the binding of an unlabeled interaction partner is detected. In this study MST measurements were used to determine the dissociation constant of the well-known in vitro CK2 substrate α S1 -casein [ 35 ] with CK2α ( Figure 10 ).…”

“…For the determination of the K D value of CK2α and α S1 -casein the Monolith NT.115 (NanoTemper Technologies GmbH, München, Germany) was used. Protein α S1 -casein was purified as described by Vordenbäumen et al [ 35 ]. First the CK2α-pAzF was coupled to DBCO-Sulfo-Cy5 via SPAAC click reaction (3.5).…”

Caseins as Regulators of Hematopoiesis

“…The Vordenbaumen group demonstrated that macrophages of human origin could be stimulated by human αS1-casein to produce GM-CSF and that αS1-casein activated the p38 MAPK pathway, which is an important signal in cells of hematopoietic origin. Interestingly, this group found that αS1-casein was linked to specific receptors for the protein in most of the macrophages analyzed and not only that but also that it could induce the production of IL-1 and IL-6, which positions it as an excellent immunomodulatory protein [48]. This same group subsequently demonstrated that αS1-casein in human milk has the ability to differentiate human monocytes from macrophages, and they also increase the phagocytic capacity of the monocytes in vitro once stimulated with the protein [49].…”

“…Human unphosphorylated αS1-casein induces Toll-like receptor 4 (TLRs) mediated expression of the proinflammatory cytokines IL-1β, GM-CSF, and IL-6 in monocytic cells [63] and induces the differentiation of monocytes toward macrophages [49,64], but this process is not dependent upon LPS. Interestingly, a posttranslational modification in αS1-casein (a phosphorylation event) inhibits binding to TLR4, which acts as an off switch for proinflammatory effects [48]. Ectopic expression (outside the mammary gland) of αS1-casein has been detected in inflamed tissues such as synovial cells and cartilage of rheumatoid arthritis, osteoarthritis, and multiple sclerosis patients [63,[65][66][67], prostate hyperplasia [68], and lymph nodes of encephalomyelitic mice [67].…”