Artikel
β-Casein induces inflammatory mediators in synovial fibroblasts and is highly expressed in synovial tissues of RA patients
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Autoren
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Nadine Honke
- Department of Rheumatology, Hiller Research Center Rheumatology, University Hospital Düsseldorf, Düsseldorf
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Tim Appel
- Department of Rheumatology, Hiller Research Center Rheumatology, University Hospital Düsseldorf, Düsseldorf
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Julia Bröcker
- Department of Rheumatology, Hiller Research Center Rheumatology, University Hospital Düsseldorf, Düsseldorf
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Georg Pongratz
- Department of Rheumatology, Hiller Research Center Rheumatology, University Hospital Düsseldorf, Düsseldorf; Center for Rheumatologic Rehabilitation, Asklepios Clinic, Bad Abbach; Department of Internal Medicine I, University Hospital Regensburg, Regensburg
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Matthias Schneider
- Department of Rheumatology, Hiller Research Center Rheumatology, University Hospital Düsseldorf, Düsseldorf
| Veröffentlicht: | 31. August 2022 |
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Gliederung
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Introduction: Background/Purpose: Casein, the largest group of protein in milk, has not only a nutritional function, but also exhibits immunostimulatory properties. While αS1-Casein (CSN1S1) is overexpressed in synovial tissues of rheumatoid arthritis (RA) and osteoarthritis (OA) patients and induces the secretion of proinflammatory cytokines in human monocytes and synovial fibroblasts, β-Casein (CSN2) is associated with autoimmune diseases, like multiple sclerosis and diabetes. In addition, there is evidence that B lymphocytes are modulated by β-casein via TLR4. In this study, we aimed to investigate whether β-casein also affects synovial fibroblasts from RA (RASF) and OA (OASF) patients in a TLR4-dependent manner and whether it is expressed in synovial tissues from RA and OA patients.
Methods: Fibroblasts were isolated from synovial tissue obtained from patients diagnosed with OA and RA, who underwent synovectomy due to total joint replacement. OASF and RASF were cultivated with prokaryotic recombinant human β-Casein in the presence and absence of a TLR4 stimulus or TLR4-signal inhibitor. After 24h, Fibroblast-derived IL-6, IL-8, and MMP-3 production was measured in the supernatant by ELISA. β-Casein expression was analyzed in synovial tissue of RA and OA patients by immunofluorescence histology.
Results: OASF and RASF up-regulate inflammatory mediators after exposure to β-Casein in a concentration-dependent manner. As inflammatory mediators IL-6, IL-8, and MMP-3 were measured in the supernatant of cultured fibroblasts (IL-6, IL-8, MMP-3: Ctrl. vs. β-Casein; n=5, RASF, OASF: p****<0.0001). Blocking of TLR4 (LPS-RS ultrapure) and its signaling (CLI-095) significantly reduced the β-Casein-induced secretion of the pro-inflammatory cytokines IL-6 and IL-8 (β-Casein vs. LPS-RS ultrapure + β-Casein, n=4, IL-6: RASF, OASF: p****<0.0001, IL-8: RASF: p****<0.0001, OASF: p***<0.0008. β-Casein vs. CLI-095 + β-Casein, n=3, IL6, IL-8: RASF, OASF: p****<0.0001). Furthermore, immunofluorescence studies of synovial tissue of RA patients showed elevated CSN2+CD3+-infiltrating T cells.
Conclusion: In summary, our results show that β-Casein induces an inflammatory and destructive phenotype in OASF and RASF via TLR4 signaling and is furthermore highly expressed in the synovial tissue of RA patients, especially in presumably infiltrating T cells. These results suggest that β-Casein may play an important role in the development and/or maintenance of a rheumatoid arthritis.
