The activation of protein kinase C induces higher production of reactive oxygen species by mononuclear cells in patients with multiple sclerosis than in controls

Autor: L. Shawver, O. Vladimirova, F. M. Lu, B. Kalman
Rok vydání: 1999
Předmět:
Zdroj: Inflammation Research. 48:412-416
ISSN: 1420-908X
1023-3830
Popis: Objective: Recent findings have increasingly shown the importance of reactive oxygen species (ROS) in causing oxidative damage to macromolecules and in contributing to tissue degeneration in target organs of autoimmune diseases. This study was aimed at comparing the base line and induced production of ROS by peripheral blood mononuclear cells (PB MNCs) of patients with multiple sclerosis (MS) in remission and relapse, of patients with other neurological diseases (OND) and of healthy controls. In addition, we analyzed the underlying mechanism of ROS production.¶Methods: PB MNCs were separated from 28 MS patients in remission and 13 in relapse, and from 29 healthy controls and 10 OND. ROS was measured by spectrofluorometry. Expression of proinflammatory cytokines was assessed by semiquantitative reverse transcription polymerase chain reaction (RT-PCR). Mitochondrial (mt) DNA haplotypes were determined by using restriction site polymorphism analysis.¶Results: The base line and tumor necrosis factor (TNF)-α or interferon (IFN)-γ induced ROS values were similar in the four groups, and the individual measures did not show a correlation with MS associated mtDNA haplotypes. Phorbol ester activation of protein kinase C (PKC) induced higher ROS production in all groups, however, with significantly greater values in the MS remission group. Calphostine C, a PKC inhibitor decreased or eliminated ROS production in a dose-dependent manner, suggesting further that it was predominantly or exclusively generated by PKC activated NADPH oxidase. A trend of increased TNF-α and IFN-γ expression was noted in the MS relapse group, in contrast to the high ROS release in the MS remission group.¶Conclusion: The detected phase difference between the highest ROS production vs TNF-α expression is compatible with the hypothesis that different subpopulations of monocytes/macrophages are involved. We suggest that the ROS producing subpopulation preferentially migrates into the central nervous system (CNS) during a relapse. The present study together with our previous observation on oxidative damage to DNA in active plaques delineates a molecular pathway likely involved in the histologic evolution of inflammatory demyelination.
Databáze: OpenAIRE
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