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Differential Effects of Inhibitor Combinations on Lysophosphatidic Acid-Mediated Chemokine Secretion in Unprimed and Tumor Necrosis Factor-α-Primed Synovial Fibroblasts
Lysophosphatidic acid (LPA) is a pleiotropic bioactive lysophospholipid involved in inflammatory mediator synthesis. Signaling through p38MAPK, ERK, Rho kinase, and MSK-CREB contributes to LPA-mediated IL-8 production in fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients. The...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702485/ https://www.ncbi.nlm.nih.gov/pubmed/29209219 http://dx.doi.org/10.3389/fphar.2017.00848 |
Sumario: | Lysophosphatidic acid (LPA) is a pleiotropic bioactive lysophospholipid involved in inflammatory mediator synthesis. Signaling through p38MAPK, ERK, Rho kinase, and MSK-CREB contributes to LPA-mediated IL-8 production in fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients. The study was undertaken to investigate how LPA activates MSKs and how signaling crosstalk between TNFα and LPA contributes to the super-production of cytokines/chemokines. RAFLS pretreated or not with TNFα were stimulated with LPA. Immunoblotting with phospho-antibodies monitored MSK activation. Cytokine/chemokine production was measured using ELISA and multiplex immunoassays. LPA induced MSK activation by signaling through ERK whereas p38MAPK, Rho kinase, NF-κB or PI3K contribute to IL-8 synthesis mainly via MSK-independent pathways. Priming with TNFα enhanced LPA-mediated MSK phosphorylation and cytokine/chemokine production. After priming with TNFα, inhibition of ERK or MSK failed to attenuate LPA-mediated IL-8 synthesis even if the MSK-CREB signaling axis was completely or partially inhibited. In TNFα-primed cells, inhibition of LPA-mediated cytokine/chemokine synthesis required a specific combination of inhibitors such as p38MAPK and ERK for IL-8 and IL-6, and Rho kinase and NF-κB for MCP-1. The ability of the signaling inhibitors to block LPA induced cytokine/chemokine synthesis is dependent on the inflammatory cytokinic environment. In TNFα-primed RAFLS the super-production of IL-8 and IL-6 induced by LPA occurs mainly via MSK-independent pathways, and simultaneous inhibition of at least two MAPK signaling pathways was required to block their synthesis. Since simultaneous inhibition of both the p38MAPK and ERK-MSK-CREB pathways are required to significantly reduce LPA-mediated IL-8 and IL-6 production in TNFα-preconditioned RAFLS, drug combinations targeting these two pathways are potential new strategies to treat rheumatoid arthritis. |
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