Abstract
Objective:
TNFα plays a crucial role in rheumatoid arthritis (RA) by stimulating fibroblast-like synoviocytes (FLS). Lymphotoxin α (LTα) is a pro-inflammatory cytokine with significant homology to TNFα. We compared the effects of both cytokines on cultured RA FLS.
Methods:
Receptor expression on RA FLS was analyzed by FACS. Cells were stimulated with LTα or TNFα and proliferation was measured by [3H]thymidine incorporation and secretion of inflammatory cytokines and metalloproteinase 3 by ELISA. Activation of MAP kinases and Akt was analyzed by Western blotting. Nuclear translocation of NFκB was visualized by immunofluorescence.
Results:
60-80% and 30-50% of the RA FLS tested expressed TNF receptors I and II, respectively, and 70-75% expressed HVEM. LTα induced RA FLS proliferation at the same level of TNFα, which was blocked by etanercept. Both LTα and TNFα induced activation of MAP kinases ERK1/2 and p38 as well as Akt. 95-98% of FLS showed nuclear translocation of NFκB after stimulation with either cytokines. LTα and TNFα were potent to induce secretion of IL-6, IL-8 and metalloproteinase 3 in FLS.
Conclusion:
LTα is as effective as TNFα in stimulating RA FLS. Blocking both cytokines might allow a better control of inflammation and synovial proliferation in RA.
Copyright © 2010 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Arthritis, Rheumatoid / pathology*
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Cell Proliferation / drug effects
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Cytokines / metabolism*
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Enzyme Activation / drug effects
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Etanercept
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Fibroblasts / drug effects
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Fibroblasts / enzymology
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Fibroblasts / metabolism*
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Fibroblasts / pathology
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Humans
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Immunoglobulin G / pharmacology
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Inflammation Mediators / metabolism*
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Lymphotoxin-alpha / pharmacology*
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Matrix Metalloproteinase 3 / metabolism
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NF-kappa B / metabolism
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Protein Kinase Inhibitors / pharmacology
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Protein Transport / drug effects
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Proto-Oncogene Proteins c-akt / metabolism
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Member 14 / metabolism
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Receptors, Tumor Necrosis Factor, Type I / metabolism
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Receptors, Tumor Necrosis Factor, Type II / metabolism
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Synovial Fluid / cytology*
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Synovial Fluid / drug effects
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Cytokines
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Immunoglobulin G
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Inflammation Mediators
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Lymphotoxin-alpha
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NF-kappa B
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Protein Kinase Inhibitors
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Member 14
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Receptors, Tumor Necrosis Factor, Type I
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Receptors, Tumor Necrosis Factor, Type II
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TNFRSF14 protein, human
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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p38 Mitogen-Activated Protein Kinases
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MMP3 protein, human
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Matrix Metalloproteinase 3
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Etanercept