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 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.
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 24 November 2017.
All research outputs
#17,920,654
of 23,008,860 outputs
Outputs from Frontiers in Pharmacology
#7,193
of 16,314 outputs
Outputs of similar age
#305,426
of 437,733 outputs
Outputs of similar age from Frontiers in Pharmacology
#107
of 252 outputs
Altmetric has tracked 23,008,860 research outputs across all sources so far. This one is in the 19th percentile – i.e., 19% of other outputs scored the same or lower than it.
So far Altmetric has tracked 16,314 research outputs from this source. They receive a mean Attention Score of 5.0. This one is in the 48th percentile – i.e., 48% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 437,733 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 25th percentile – i.e., 25% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 252 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 50% of its contemporaries.
