The activity of JAK-STAT pathways in rheumatoid arthritis: constitutive activation of STAT3 correlates with interleukin 6 levels
| Autor: | Ilkka Junttila, Markku Korpela, Olli Silvennoinen, Krista-Liisa Vidqvist, P. Isomäki |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Adult
Male STAT3 Transcription Factor medicine.medical_specialty T-Lymphocytes medicine.medical_treatment Monocytes Arthritis Rheumatoid Interferon-gamma Interleukin 21 Immune system Rheumatology Internal medicine Humans Medicine Pharmacology (medical) RNA Messenger STAT1 Phosphorylation Interleukin 6 STAT3 Aged Janus Kinases Aged 80 and over biology Interleukin-6 business.industry JAK-STAT signaling pathway T lymphocyte Middle Aged Flow Cytometry Interleukin-10 STAT1 Transcription Factor Endocrinology Cytokine Case-Control Studies biology.protein Cancer research Female business Signal Transduction |
| Zdroj: | Rheumatology. 54:1103-1113 |
| ISSN: | 1462-0332 1462-0324 |
| DOI: | 10.1093/rheumatology/keu430 |
| Popis: | Objective Many cytokines involved in RA activate the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways. Therapeutic drugs that inhibit these pathways are being developed for RA. To investigate disease-related alterations in the activity of JAK-STAT pathways in RA, we studied the expression and activation of STAT1 and STAT3 in unstimulated and cytokine-stimulated cells and determined the levels of circulating cytokines. Methods The expression of STAT1 and STAT3 mRNA in peripheral blood (PB) and SF T cells and monocytes was studied in RA patients and healthy volunteers by RT-PCR. Basal and cytokine (IFN-γ, IL-6, IL-10)-induced STAT phosphorylation was analysed in PB T cells and monocytes using multicolour flow cytometric analysis. Results STAT3 mRNA levels were up-regulated in both PB and SF T cells and monocytes from RA patients. STAT1 expression was elevated in SF monocytes. The levels of phospho-STAT3 in resting PB T cells and monocytes were significantly higher in patients with RA than in healthy volunteers. IL-6 levels were elevated in RA plasma and correlated with the level of STAT3 phosphorylation in CD4(+) T cells and monocytes. IL-6-mediated STAT3 activation was deregulated in T cells from RA patients. IL-6-induced phosphorylation of STAT3 was decreased in CD4(+) T cells from patients with high plasma IL-6 levels and constitutive STAT3 phosphorylation. Conclusion The results suggest that IL-6 induces hyperactivation of STAT3 in circulating immune cells in active RA, and this subsequently desensitizes the IL-6 response in T cells. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|