Divergent effects of infliximab and anakinra therapies on macrophage phenotype from patients with refractory rheumatoid arthritis.
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 TNFalpha 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.
Pham
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TN
Division of BioMedical Sciences, Faculty of Medicine, Memorial University, St John's, Newfoundland, Canada.
Rahman
P
P
Richardson
V J
VJ
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D006801:Humans; D000069285:Infliximab; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use*; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000097:blood; D052247:Nitric Oxide Synthase Type II / Q000097:blood; D010641:Phenotype; D011493:Protein Kinase C / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D000069285:Infliximab; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; C081975:protein kinase C eta; D011493:Protein Kinase C