Lucie Andrés Cerezo1, Martina Remáková1, Michal Tomčik1, Steffen Gay1, Michel Neidhart1, Eugene Lukanidin1, Karel Pavelka1, Mariam Grigorian1, Jiří Vencovský1, Ladislav Šenolt2. 1. Institute of Rheumatology and Department of Rheumatology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic, Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland and Neuro-oncology Group, Laboratory of Neural Plasticity, Department of Neuroscience and Pharmacology, Faculty of Health Sciences, Copenhagen University, Copenhagen, Denmark. 2. Institute of Rheumatology and Department of Rheumatology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic, Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland and Neuro-oncology Group, Laboratory of Neural Plasticity, Department of Neuroscience and Pharmacology, Faculty of Health Sciences, Copenhagen University, Copenhagen, Denmark. senolt@revma.cz.
Abstract
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.
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.
Authors: Barbora Šumová; Lucie Andrés Cerezo; Lenka Szczuková; Lucie Nekvindová; Michal Uher; Hana Hulejová; Radka Moravcová; Mariam Grigorian; Karel Pavelka; Jiří Vencovský; Ladislav Šenolt; Jakub Závada Journal: Rheumatol Int Date: 2018-11-03 Impact factor: 2.631
Authors: Jia-Bin Sun; Jan Holmgren; Maximilian Larena; Manuela Terrinoni; Yu Fang; Anne R Bresnick; Zou Xiang Journal: Front Immunol Date: 2017-09-11 Impact factor: 7.561