Artikel
Inhibition of janus kinases abrogates the IFNγ-induced activation of the focal adhesion kinase
Suche in Medline nach
Autoren
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Thomas Karonitsch
- Medizinische Universität Wien, Klinik für Innere Medizin 3, Klinische Abteilung für Rheumatologie, Wien, Österreich
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Denise Beckmann
- Universitätsklinikum Münster, Westfälische Wilhelms-Universität, Institut für Experimentelle Muskuloskelettale Medizin, Münster
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Christina Wunrau
- Universitätsklinikum Münster, Westfälische Wilhelms-Universität, Institut für Experimentelle Muskuloskelettale Medizin, Münster
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Karoline Dalwigk
- Medizinische Universität Wien, Klinische Abteilung für Rheumatologie, Wien, Österreich
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Birgit Niederreiter
- Medizinische Universität Wien, Klinische Abteilung für Rheumatologie, Wien, Österreich
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Johannes Holinka
- Univ. Klinik für Orthopädie Medizinische Universität Wien, Wien, Österreich
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Günter Steiner
- Medizinische Universiät Wien, Klinik für Innere Medizin 3, Abteilung für Rheumatologie, Wien, Österreich
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Josef Smolen
- Medizinische Universität Wien, Klinische Abteilung für Rheumatologie, Wien, Österreich
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Thomas Pap
- Universitätsklinikum Münster, Westfälische Wilhelms-Universität, Institut für Experimentelle Muskuloskelettale Medizin, Münster
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Hans Kiener
- Medizinische Universität Wien, Klinische Abteilung für Rheumatologie, Wien, Österreich
| Veröffentlicht: | 29. August 2016 |
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Gliederung
Text
Background: While evidence implicates both the adaptive and innate immune system in rheumatoid arthritis (RA) pathogenesis, accumulating data indicate that the synovial tissue itself actively participates in the destructive inflammatory process. Specifically, resident fibroblast-like synoviocytes (FLS), together with macrophages, re-organize to form an aggressive cell mass, called pannus, which destroys the articular cartilage and the subchondral bone. The exact molecular mechanisms of synovial pannus formation, FLS expansion and invasion into adjacent tissues are not yet known. Our data strongly suggest that the T-cell derived cytokine IFNγ is involved in joint destruction facilitated by FLS.
Methods: Human synovial tissues from RA patients were obtained as discarded specimens following synovectomy. Synoviocyte cell suspensions were prepared from synovial tissues by mincing, followed by digestion with collagenase. FLS were used between passages 4 and 8. Migration- (modified Boyden chamber) and invasion assays (MARTIN assay) were performed to demonstrate a role for IFNγ in facilitating pannus formation. Western blot analyses were applied to determine the influence of IFNγ on focal adhesion kinase (FAK) activity.
Results: Migration and invasion assays revealed increased migratory activity for IFNγ-stimulated FLS, compared to unstimulated FLS. Biochemical studies showed that IFNγ promotes the migratory and invasive activity of FLS, most probably via the focal adhesion kinase (FAK), a kinase which is very well known to regulate cell migration and invasion. In more detail, IFNγ stimulation specifically resulted in the phosphorylation of FAK-Y925, a phosphosite that has recently been shown to be required for FAK-mediated cell migration. To determine if JAK activation is required for IFNγ-induced FAK activation we next silenced JAK1 and JAK2 expression with specific siRNA pools. Interestingly, the knockdown of JAK2, but not JAK1, abrogated the IFNγ induced activation of FAK. Correspondingly, baricitinib and tofacitinib, two well known JAK-inhibitors, abrogated FAK activation by IFNγ.
Conclusion: In conclusion our study contributes insight into the synovial response to IFNγ and reveals JAKs and FAK as potential targets for synoviocyte-mediated joint destruction in arthritis.
