Rheumatoid Arthritis: Trajkovic V

Miljkovic D, Trajkovic V. · Institute for Biological Research, Belgrade, Serbia and Montenegro. · Cytokine Growth Factor Rev. · Pubmed #14746811 No free full text.

Abstract: Interleukin-17 (IL-17) is a proinflammatory T cell cytokine presumably involved in physiological responses to infection, but also in immunopathology of autoimmune disorders such as rheumatoid arthritis. The proinflammatory action of IL-17 depends considerably on its ability to trigger the expression of inducible nitric oxide (NO) synthase (iNOS), an enzyme responsible for the generation of cytotoxic and immunoregulatory free radical NO. Here we discuss the role of IL-17 in the cytokine network controlling iNOS expression, and analyze signaling pathways employed by IL-17 for the initiation of iNOS gene transcription. We also propose biological consequences of IL-17-mediated NO release that could be relevant for the mechanisms or therapy of autoimmune and inflammatory disorders.

Miljkovic Dj, Cvetkovic I, Stosic-Grujicic S, Trajkovic V. · Institute for Biological Research Sinisa Stankovic, School of Medicine, University of Belgrade, Belgrade, Yugoslavia. · Clin Exp Immunol. · Pubmed #12699411 links to  free full text

Abstract: Mycophenolate mofetil (MMF) is an immunosuppressive drug that acts as a selective inhibitor of inosine monophosphate dehydrogenase (IMPDH). MMF has recently been shown to inhibit the enzymatic activity of inducible NO synthase (iNOS) and subsequent production of the cytotoxic free radical nitric oxide (NO) in endothelial cells. We here investigated the effect of bioactive MMF compound mycophenolic acid (MPA) on iNOS-mediated NO synthesis in fibroblasts, which are important source of NO in rheumatoid arthritis and during rejection of solid organ transplants. MPA exerted dose-dependent inhibition of NO synthesis, measured as nitrite accumulation, in IFN-gamma + LPS-stimulated L929 mouse fibroblast cell line and rat primary fibroblasts. The effect of MPA was not mediated through interference with IMPDH-dependent synthesis of iNOS co-factor BH4 and subsequent suppression of iNOS enzymatic activity, as direct BH4 precursor sepiapterin failed to block the action of the drug. MPA suppressed the IFN-gamma + LPS-induced expression of fibroblast iNOS protein, as well as mRNA for iNOS and its transcription factor IRF-1, as assessed by cell-based ELISA and semiquantitative RT-PCR, respectively. MPA suppression of fibroblast NO release, iNOS, and IRF-1 activation, was efficiently prevented by exogenous guanosine, indicating that the drug acted through reduction of IMPDH-dependent synthesis of guanosine nucleotides. These results suggest that MPA inhibits NO production in fibroblasts by blocking guanosine nucleotide-dependent expression of iNOS gene, through mechanisms that might involve the interference with the induction of iNOS transcription factor IRF-1.