期刊
INTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY
卷 23, 期 2, 页码 491-501出版社
SAGE PUBLICATIONS INC
DOI: 10.1177/039463201002300211
关键词
rheumatoid arthritis; inflammation; inducible nitric oxide synthase; NOS2; monocyte; macrophage; phenotype; nitric oxide; PKC-eta; anakinra; IL-1Ra; infliximab; anti-TNF-alpha
资金
- Memorial University
- Faculty of Medicine Research and Development Fund
- TNQP
Previously, we documented the co-expression of the inducible nitric oxide synthase (NOS2) and protein kinase C-eta (PKC-eta) in peripheral blood-derived macrophages (PBDM) from moderate to severe rheumatoid arthritis (RA) patients with elevated plasma nitric oxide levels but not from those with non-inflammatory osteoarthritis (OA) or normal plasma NO levels. The presence of PKC-eta was found to be required before macrophages could acquire the NOS2-positive phenotype and make copious levels of NO. In the current study, we report the divergent effects of two biological-based RA therapies which target TNF alpha function (infliximab) or IL1 response (anakinra) on the development of the NOS2-positive phenotype by PBDM in patients with refractory RA. Both infliximab and anakinra were effective in improving disease symptoms. However, treatment with anakinra, but not infliximab led to a complete suppression of NOS2 expression in PBDM and consequently, a more pronounced reduction in plasma NO levels. Data also revealed a requirement of both TNF-alpha and IL-1 in the development of the NOS2-positive macrophage phenotype. Finally, the data have shed light on the molecular mechanisms by which NO production may be regulated during disease progression to severe RA, and thus, offer a novel insight into the identification of future therapeutic targets for the treatment of inflammatory diseases.
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