Abstract
Protein I/II, a pathogen-associated molecular pattern from oral streptococci, is a potent inducer of interleukin-6 (IL-6) and IL-8 synthesis and release from fibroblast-like synoviocytes (FLSs), cells that are critically involved in joint inflammation. This synthesis implicates ERK 1/2 and JNKs as well as AP-1-binding activity and nuclear translocation of NF-kappaB. The mechanisms by which protein I/II activates MAPKs remain, however, elusive. Because focal adhesion kinase (FAK) was proposed to play a role in signaling to MAPKs, we examined its ability to contribute to the MAPKs-dependent synthesis of IL-6 and IL-8 in response to protein I/II. We used FAK-/- fibroblasts as well as FAK+/+ fibroblasts and FLSs transfected with FRNK, a dominant negative form of FAK. The results demonstrate that IL-6 and IL-8 release in response to protein I/II was strongly inhibited in both protein I/II-stimulated FAK-/- and FRNK-transfected cells. Cytochalasin D, which inhibits protein I/II-induced phosphorylation of FAK (Tyr-397), had no effect either on activation of ERK 1/2 and JNKs or on IL-6 and IL-8 release. Taken together, these results indicate that IL-6 and IL-8 release by protein I/II-activated FLSs is regulated by FAK independently of Tyr-397 phosphorylation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus
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Androstadienes / pharmacology
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Antibodies, Monoclonal / metabolism
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Blotting, Western
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Cells, Cultured
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Fibroblasts / metabolism*
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Focal Adhesion Kinase 1
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Focal Adhesion Protein-Tyrosine Kinases
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Genes, Dominant
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Humans
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Inflammation
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Integrin alpha5beta1 / metabolism
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Interleukin-6 / biosynthesis*
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Interleukin-8 / biosynthesis*
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Interleukin-8 / metabolism
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism*
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NF-kappa B / metabolism
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Nucleic Acid Synthesis Inhibitors / pharmacology
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Phosphorylation
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Protein Synthesis Inhibitors / pharmacology
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Protein-Tyrosine Kinases / metabolism
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Protein-Tyrosine Kinases / physiology*
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RNA, Messenger / metabolism
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Signal Transduction
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Synovial Membrane / cytology*
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Time Factors
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Tyrosine / metabolism
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Wortmannin
Substances
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Androstadienes
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Antibodies, Monoclonal
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Enzyme Inhibitors
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Integrin alpha5beta1
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Interleukin-6
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Interleukin-8
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NF-kappa B
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Nucleic Acid Synthesis Inhibitors
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Protein Synthesis Inhibitors
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RNA, Messenger
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Tyrosine
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Protein-Tyrosine Kinases
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Focal Adhesion Kinase 1
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Focal Adhesion Protein-Tyrosine Kinases
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PTK2 protein, human
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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Wortmannin