Regulation of the interferon‐α production induced by RNA‐containing immune complexes in plasmacytoid dendritic cells
ML Eloranta, T Lövgren, D Finke… - … : Official Journal of …, 2009 - Wiley Online Library
ML Eloranta, T Lövgren, D Finke, L Mathsson, J Rönnelid, B Kastner, GV Alm, L Rönnblom
Arthritis & Rheumatism: Official Journal of the American College …, 2009•Wiley Online LibraryObjective Interferon‐α (IFNα) is produced in several autoimmune diseases, including
systemic lupus erythematosus (SLE), and may be important in their pathogenesis. We
undertook this study to investigate how IFNα production induced by RNA‐containing
immune complexes (ICs) in plasmacytoid dendritic cells (PDCs) is regulated. Methods
Normal PDCs purified from peripheral blood mononuclear cells (PBMCs) were cocultivated
with other cell populations isolated from healthy individuals or SLE patients. IFNα production …
systemic lupus erythematosus (SLE), and may be important in their pathogenesis. We
undertook this study to investigate how IFNα production induced by RNA‐containing
immune complexes (ICs) in plasmacytoid dendritic cells (PDCs) is regulated. Methods
Normal PDCs purified from peripheral blood mononuclear cells (PBMCs) were cocultivated
with other cell populations isolated from healthy individuals or SLE patients. IFNα production …
Objective
Interferon‐α (IFNα) is produced in several autoimmune diseases, including systemic lupus erythematosus (SLE), and may be important in their pathogenesis. We undertook this study to investigate how IFNα production induced by RNA‐containing immune complexes (ICs) in plasmacytoid dendritic cells (PDCs) is regulated.
Methods
Normal PDCs purified from peripheral blood mononuclear cells (PBMCs) were cocultivated with other cell populations isolated from healthy individuals or SLE patients. IFNα production was induced by RNA‐containing ICs, which consisted of anti‐RNP autoantibodies and U1 small nuclear RNP particles, and the effects of prostaglandin E2 (PGE2), reactive oxygen species (ROS), or the cytokines IFNα2b, granulocyte–macrophage colony‐stimulating factor (GM‐CSF), interleukin‐10 (IL‐10), or tumor necrosis factor α (TNFα) were explored.
Results
Monocytes inhibited IFNα production by PDCs in PBMC cultures, while natural killer (NK) cells were stimulatory. The monocytes had little effect on IFNα production by pure PDCs but inhibited its stimulation by NK cells. Monocytes from SLE patients were less inhibitory. Exposure of PBMCs or PDCs to IFNα2b/GM‐CSF increased their IFNα production. RNA‐containing ICs caused production of ROS, PGE2, and TNFα, especially in monocytes. These mediators and IL‐10 suppressed IFNα production in PBMC cultures, with ROS and PGE2 also inhibiting IFNα production by purified PDCs. Inhibition by all of these agents, except for ROS, was abolished by IFNα2b/GM‐CSF. The inhibitory effect of monocytes was significantly counteracted by the ROS scavengers serotonin and catalase.
Conclusion
IFNα production induced by RNA‐containing ICs in PDCs is regulated by a network of interactions between monocytes, NK cells, and PDCs, involving several pro‐ and antiinflammatory molecules. This should be considered when designing and applying new therapies.
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