Abstract | OBJECTIVE: METHODS: In vitro studies were performed using peripheral blood macrophages derived from healthy donors and treated with TNF and using synovial fluid macrophages derived from patients with RA. Levels of activated STAT proteins and other transcription factors were detected by Western blotting, and gene expression was measured by real-time polymerase chain reaction analysis. The in vivo effects of JAK inhibitors were evaluated in the K/BxN serum-transfer model of arthritis. RESULTS:
JAK inhibitors suppressed the activation and expression of STAT-1 and downstream inflammatory target genes in TNF-stimulated and RA synovial macrophages. In addition, JAK inhibitors decreased nuclear localization of NF-κB subunits in TNF-stimulated and RA synovial macrophages. CP-690,550 significantly decreased the expression of interleukin-6 in synovial macrophages. JAK inhibitors augmented nuclear levels of NF-ATc1 and cJun, followed by increased formation of osteoclast-like cells. CP-690,550 strongly suppressed K/BxN serum-transfer arthritis, which is dependent on macrophages, but not lymphocytes. CONCLUSION: Our findings demonstrate that JAK inhibitors suppress macrophage activation and attenuate TNF responses and further suggest that suppression of cytokine/ chemokine production and innate immunity contribute to the therapeutic efficacy of JAK inhibitors.
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Authors | Anna Yarilina, Kai Xu, Chunhin Chan, Lionel B Ivashkiv |
Journal | Arthritis and rheumatism
(Arthritis Rheum)
Vol. 64
Issue 12
Pg. 3856-66
(Dec 2012)
ISSN: 1529-0131 [Electronic] United States |
PMID | 22941906
(Publication Type: Journal Article)
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Copyright | Copyright © 2012 by the American College of Rheumatology. |
Chemical References |
- Enzyme Inhibitors
- Interleukin-6
- NF-kappa B
- NFATC Transcription Factors
- Nitriles
- Piperidines
- Proto-Oncogene Proteins c-jun
- Pyrazoles
- Pyrimidines
- Pyrroles
- STAT1 Transcription Factor
- Tumor Necrosis Factor-alpha
- ruxolitinib
- tofacitinib
- Janus Kinases
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Topics |
- Animals
- Arthritis, Rheumatoid
(drug therapy, metabolism, pathology)
- Cells, Cultured
- Disease Models, Animal
- Enzyme Inhibitors
(pharmacology)
- Humans
- In Vitro Techniques
- Inflammation
(metabolism)
- Interleukin-6
(metabolism)
- Janus Kinases
(antagonists & inhibitors)
- Macrophages
(drug effects, metabolism, pathology)
- Mice
- Mice, Inbred C57BL
- NF-kappa B
(metabolism)
- NFATC Transcription Factors
(metabolism)
- Nitriles
- Piperidines
- Proto-Oncogene Proteins c-jun
(metabolism)
- Pyrazoles
(pharmacology)
- Pyrimidines
(pharmacology, therapeutic use)
- Pyrroles
(pharmacology, therapeutic use)
- STAT1 Transcription Factor
(metabolism)
- Signal Transduction
(drug effects)
- Synovial Membrane
(drug effects, metabolism, pathology)
- Tumor Necrosis Factor-alpha
(pharmacology)
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