ABSTRACT
OBJECTIVES: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder, primarily affecting the articular structures and synovial membranes of multiple joints. Beside pharmacologically based treatments, sulphur bath therapy has long been used as a therapy for patients suffering from different rheumatic disorders. But scientific reports about the beneficial effects of H(2)S as well as about the underlying molecular mechanisms are controversial and rare. METHODS: Fibroblast-like synoviocytes (FLS) derived from RA and OA-patients were treated with the H(2)S-donor sodium hydrogen sulphide (NaHS). IL-6 release was quantified by enzyme-linked immunosorbent assay (ELISA). Gene expression of IL-6, IL-8 and COX-2 as well as of the matrix metalloproteinases (MMPs) MMP-2, MMP-3 and MMP-14 was monitored by quantitative real-time PCR (qRT-PCR). Modulation of the mitogen-activated protein kinases (MAPKs) p38 and ERK1/2 was analysed by Western blotting. RESULTS: High concentrations of H(2)S (above 0.5mM) elevated the expression of pro-inflammatory genes in RA- and OA-FLS. This was accompanied by activation of p38 and ERK1/2 MAPK. H(2)S-induced expression of IL-6, IL-8 and COX-2 was completely blocked by specific inhibitors of p38 and ERK1/2 MAPK and NF-κB. CONCLUSION: H(2)S is a potent gaseous molecule that can upregulate the expression of a series of pro-inflammatory genes in RA and OA-FLS. Therefore, caution is advised in patients with active RA when taking sulphur bath therapy.
Subject(s)
Arthritis, Rheumatoid/immunology , Fibroblasts/drug effects , Hydrogen Sulfide/pharmacology , Mineral Waters/therapeutic use , Osteoarthritis/immunology , Arthritis, Rheumatoid/therapy , Balneology , Cells, Cultured , Cyclooxygenase 2/genetics , Cyclooxygenase 2/metabolism , Fibroblasts/immunology , Fibroblasts/metabolism , Fibroblasts/pathology , Gene Expression Regulation/drug effects , Gene Expression Regulation/immunology , Humans , Inflammation Mediators/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Interleukin-8/genetics , Interleukin-8/metabolism , MAP Kinase Signaling System/drug effects , Matrix Metalloproteinases/genetics , Matrix Metalloproteinases/metabolism , Osteoarthritis/therapy , Sulfides/pharmacology , Synovial Membrane/pathologySubject(s)
Alternative Splicing , Artifacts , B-Lymphocytes/metabolism , PAX5 Transcription Factor/genetics , Specimen Handling , Anticoagulants/pharmacology , B-Lymphocytes/cytology , B-Lymphocytes/pathology , Blood Cells/metabolism , Bone Marrow Cells/metabolism , Burkitt Lymphoma/pathology , Cell Line, Tumor/metabolism , Cellular Senescence , Child , Edetic Acid/pharmacology , Exons/genetics , Heparin/pharmacology , Humans , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , PAX5 Transcription Factor/biosynthesis , PAX5 Transcription Factor/blood , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Protein Isoforms/biosynthesis , Protein Isoforms/blood , Protein Isoforms/genetics , TemperatureABSTRACT
The presence of a dicentric chromosome dic(9;20) has been reported to have an unfavourable prognosis in children with B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). As outcome may be influenced by type and composition of treatment, we analyzed 19 BCP-ALL patients with dic(9;20) who have been treated with ALL-BFM (Berlin-Frankfurt-Münster) protocols that included a 4-drug induction and subsequent consolidation therapy. All patients were good responders to prednisone and in complete remission after induction therapy. Eight patients had no molecular disease after induction and another eight patients had levels < or =10(-4) after consolidation therapy. After a median follow-up of 3.4 years, probabilities of 5-year event-free and overall survival were 75 +/- 11% and 94 +/- 6%, respectively. Of note, there was a tendency for extramedullary disease in case of relapse (two of three relapses with central nervous system involvement). In conclusion, in the context of ALL-BFM protocols dic(9;20)-positivity appeared to have a favourable prognosis, which could be due to a dose- and time-intensified induction and induction consolidation therapy. Given that in vitro studies have shown high cellular sensitivity of dic(9;20)-positive leukemic blasts to l-asparaginase and cytarabine, it is reasonable to speculate that both drugs, as given early during BFM-like induction and consolidation therapy, may have contributed to this good outcome.
