In inflammation, inducible nitric oxide synthase (iNOS) produces nitric oxide (NO), which modulates inflammatory processes. We investigated the effects of Janus kinase (JAK) inhibitors, AG-490 and WHI-P154, on iNOS expression and NO production in J774 murine macrophages stimulated with interferon-gamma (IFN-gamma). JAK inhibitors AG-490 and WHI-P154 decreased IFN-gamma-induced nuclear levels of signal transducer and activator of transcription 1alpha (STAT1alpha). JAK inhibitors AG-490 and WHI-P154 decreased also iNOS protein and mRNA expression and NO production in a concentration-dependent manner. Neither of the JAK inhibitors affected the decay of iNOS mRNA when determined by actinomycin D assay. Our results suggest that the inhibition of JAK-STAT1-pathway by AG-490 or WHI-P154 leads to the attenuation of iNOS expression and NO production in IFN-gamma-stimulated macrophages.
Rheumatoid arthritis is a chronic systemic inflammatory disease with major articular manifestations. While its aetiology still remains to be resolved, our understanding on the pathogenesis of rheumatoid arthritis has become clearer during two decades enlightening the role of adaptative immunity in the development of the symptoms and signs as well as in the progression of the pathological articular changes taking place in inadequately controlled disease. T lymphocytes are considered to be an important cell type in the pathogenesis of rheumatoid arthritis through production of proinflammatory cytokines, promotion of formation of ectopic lymphoid structures and neovascularization in synovial tissue, promotion autoantibody production by B cells, and activation of synoviocytes and osteoclasts. Abatacept, a CTLA4-Ig fusion protein, represents a new therapeutic approach in rheumatoid arthritis. Abatacept attenuates T cell activation as it regulates the activation of T cells by inhibiting the CD80/86:CD28 co-stimulatory pathway that is required for the proper T cell activation. This MiniReview gives an overview on the mechanism of action of abatacept and summarizes the published clinical data on abatacept in the treatment of rheumatoid arthritis.
In inflammation, pro-inflammatory cytokines and bacterial products induce the production of high amounts of NO by inducible nitric oxide synthase (iNOS) in inflammatory and tissue cells. NO is an effector molecule in innate immunity, and it also has regulatory and pro-inflammatory/destructive effects in the inflammatory process. Protein kinase Cδ (PKCδ) is an important signaling protein regulating B lymphocyte functions, but less is known about its effects in innate immunity and inflammatory gene expression. In the present study we investigated the role of PKCδ in the regulation of iNOS expression in inflammatory conditions. NO production and iNOS expression were induced by LPS or a combination of cytokines IFNγ, IL-1β, and TNFα. Down-regulation of PKCδ by siRNA and inhibition of PKCδ by rottlerin suppressed NO production and iNOS expression in activated macrophages and fibroblasts. PKCδ directed siRNA and inhibition of PKCδ by rottlerin suppressed also the expression of transcription factor IRF1, possibly through inhibition of STAT1 activation. Accordingly, down-regulation of IRF1 by siRNA reduced iNOS expression in response to inflammatory stimuli. In addition, inhibition of PKCδ showed anti-inflammatory effects in carrageenan induced paw inflammation in mice as did iNOS inhibitor L-NIL. These results suggest that inhibitors of PKCδ have anti-inflammatory effects in disease states complicated by enhanced NO production through iNOS pathway.
Background and purpose: Levosimendan is used in the treatment of decompensated heart failure. It increases the contractility of the myocardium by sensitizing troponin C to calcium. In addition, levosimendan has been reported to have beneficial effects in experimental models of septic shock. Because heart failure and sepsis have been associated with excessive nitric oxide (NO) production through inducible NOS (iNOS), we investigated the effects of the simendans on NO production and iNOS expression and on generation of pro‐inflammatory cytokines. Experimental approach: Macrophages and fibroblasts were exposed to inflammatory stimuli to induce iNOS expression. Proteins were measured by western blot and mRNA expression was determined by quantitative RT‐PCR. Promoter activity and nuclear factor‐κB (NF‐κB) and the γ‐activated site (GAS; binding site for signal transducer and activator of transcription 1; STAT1)‐mediated transcription were investigated using luciferase reporter constructs. Cytokines tumour necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6) were measured by ELISA. Key results: Levosimendan and dextrosimendan decreased NO production in a dose‐dependent manner in cells exposed to inflammatory stimuli. The simendans decreased iNOS protein and mRNA expression but did not affect iNOS mRNA decay. These compounds decreased iNOS promoter activity and inhibited NF‐κB‐mediated transcription but not that mediated by STAT1/GAS. The simendans reduced IL‐6 production slightly but they had no effect on TNF‐α synthesis. Conclusions and implications: The simendans downregulated NF‐κB‐dependent transcription and decreased iNOS promoter activity, iNOS expression and NO production. These mechanisms may contribute to their beneficial clinical effects. British Journal of Pharmacology (2008) 155 , 884–895; doi: 10.1038/bjp.2008.328 ; published online 18 August 2008
Rheumatoid arthritis (RA) is a chronic, autoimmune reaction-driven systemic inflammatory disease that affects joints and several other organs. Although anti-TNF therapy and combination therapy with traditional anti-rheumatic drugs have improved the treatment of RA, still quite a significant proportion of patients do not reach adequate anti-rheumatic response. The understanding of the pathogenesis of RA has developed markedly during the last two decades, and this has brought up new targets for anti-rheumatic therapy. B cells have been found to have a pivotal role in the development of arthritis both in experimental models and in humans. Rituximab, an anti-CD20 antibody that depletes B cells, has been introduced in the treatment of RA, and it has proven to be safe and efficacious in RA. This review gives an overview on the mechanism of action of rituximab in RA and summarizes the published clinical data of rituximab in the treatment of RA.
To describe a cluster of inflammatory rheumatic diseases in an office workplace that suggests the presence of an environmental trigger.There had been an indoor air problem in the workplace since the early 1990s. Large areas of the outer walls of the building were found to be moisture-damaged and contaminated by microbial growth. Case histories of the personnel were studied, and their working areas were related to the areas with highest microbial contamination. The incidence of inflammatory rheumatic diseases was compared with the statistics of the same geographic area.Ten patients with inflammatory rheumatic diseases (3 rheumatoid arthritis, 4 ankylosing spondylitis, 2 Sjögren's syndrome, and one of psoriatic arthritis) entitled to specially reimbursed medication were diagnosed in 1987-2000 (seven cases in 1995-1998). The incidence density ratio computed for the period 1987-2000 was 6.8 (95% confidence interval 3.6-13.0) for all office personnel and 13.2 (6.0-29.0) for those working close to the wall sustaining the worst damage.The accumulation of chronic inflammatory rheumatic diseases in a single workplace suggests that some environmental exposure in this damp office had triggered the diseases.
