The metastasis-associated protein S100A4 promotes the inflammatory response of mononuclear cells via the TLR4 signalling pathway in rheumatoid arthritis
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
24643522
DOI
10.1093/rheumatology/keu031
PII: keu031
Knihovny.cz E-resources
- Keywords
- RAGE, S100A4, Toll-like receptor 4, pro-inflammatory cytokines, rheumatoid arthritis,
- MeSH
- Cytokines metabolism MeSH
- Adult MeSH
- Leukocytes, Mononuclear metabolism MeSH
- Middle Aged MeSH
- Humans MeSH
- NF-kappa B metabolism MeSH
- S100 Proteins metabolism MeSH
- Arthritis, Rheumatoid metabolism MeSH
- S100 Calcium-Binding Protein A4 MeSH
- Aged MeSH
- Signal Transduction physiology MeSH
- Toll-Like Receptor 4 metabolism MeSH
- Up-Regulation physiology MeSH
- Inflammation metabolism MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Cytokines MeSH
- NF-kappa B MeSH
- S100 Proteins MeSH
- S100 Calcium-Binding Protein A4 MeSH
- S100A4 protein, human MeSH Browser
- TLR4 protein, human MeSH Browser
- Toll-Like Receptor 4 MeSH
OBJECTIVES: S100A4 has been implicated in cancer and several inflammatory diseases, including RA. The aim of the present study was to determine whether S100A4 can stimulate proinflammatory cytokine production in mononuclear cells. METHODS: Peripheral blood mononuclear cells (PBMCs) isolated from patients with RA were stimulated with S100A4, S100A8, S100A9 and S100A12. The production of IL-1β, IL-6 and TNF-α was measured by ELISA. Receptor for advanced glycation end products (RAGEs) and Toll-like receptor 4 (TLR4) signalling were examined. For signalling pathway blocking studies, inhibitors of myeloid differentiation primary response gene 88 (MyD88), nuclear factor kappa B (NF-κB) and the mitogen activated protein (MAP) kinases p38, extracellular signal-regulated kinase 1/2 (ERK1/2) and Jun N-terminal kinase (JNK) were used. MAP kinase activation was evaluated by western blotting. RESULTS: Stimulation of PBMCs with S100A4 significantly up-regulated IL-1β, IL-6 and TNF-α production compared with unstimulated cells (P < 0.001). Importantly, the production of these cytokines was markedly enhanced in response to S100A4 compared with S100A8 and S100A12; however, it was less pronounced compared with S100A9. Furthermore, enhanced production of proinflammatory cytokines in S100A4-stimulated PMBCs was at least partly mediated via TLR4, but not RAGEs, and by activation of the transcription factor NF-κB and the MAP kinases p38 and ERK1/2. CONCLUSION: This is the first study to demonstrate that S100A4 can induce an inflammatory response mediated by TLR4 and by the activation of NF-κB and the kinases p38 and ERK1/2 in mononuclear cells from patients with RA. Therefore S100A4 may be a potential therapeutic target for immune-mediated diseases.
References provided by Crossref.org
S100A4 is elevated in axial spondyloarthritis: a potential link to disease severity