A Cytokine Signalling Network for the Regulation of Inducible Nitric Oxide Synthase Expression in Rheumatoid ArthritisReportar como inadecuado

A Cytokine Signalling Network for the Regulation of Inducible Nitric Oxide Synthase Expression in Rheumatoid Arthritis - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

In rheumatoid arthritis RA, nitric oxide NO is implicated in inflammation, angiogenesis and tissue destruction. The enzyme inducible nitric oxide synthase iNOS is responsible for the localised over-production of NO in the synovial joints affected by RA. The pro- and anti-inflammatory cytokines stimulate the synovial macrophages and the fibroblast-like synoviocytes to express iNOS. Therefore, the cytokine signalling network underlying the regulation of iNOS is essential to understand the pathophysiology of the disease. By using information from the literature, we have constructed, for the first time, the cytokine signalling network involved in the regulation of iNOS expression. Using the differential expression patterns obtained by re-analysing the microarray data on the RA synovium and the synovial macrophages available in the Gene Expression Omnibus GEO database, we aimed to establish the role played by the network genes towards iNOS regulation in the RA synovium. Our analysis reveals that the network genes belonging to interferon IFN and interleukin-10 IL-10 pathways are always up-regulated in the RA synovium whereas the genes which are part of the anti-inflammatory transforming growth factor-beta TGF-β signalling pathway are mostly down-regulated. We observed a consistent up-regulation of the transcription factor signal transducers and activators of transcription 1 STAT1 in the RA synovium and the macrophages. Interestingly, we found a consistent up-regulation of the iNOS interacting protein ras-related C3 botulinum toxin substrate 2 RAC2 in the RA synovium as well as the macrophages. Importantly, we have constructed a model to explain the impact of IFN and IL-10 pathways on Rac2-iNOS interaction leading to over-production of NO and thereby causing chronic inflammation in the RA synovium. The interplay between STAT1 and RAC2 in the regulation of NO could have implications for the identification of therapeutic targets for RA.

Autor: Poulami Dey, Venugopal Panga, Srivatsan Raghunathan

Fuente: http://plos.srce.hr/


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