Systemic Lupus Erythematosus Basic Science Studies
Regulation of the interferon-α production induced by RNA-containing immune complexes in plasmacytoid dendritic cells
Article first published online: 30 JUL 2009
Copyright © 2009 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 60, Issue 8, pages 2418–2427, August 2009
How to Cite
Eloranta, M.-L., Lövgren, T., Finke, D., Mathsson, L., Rönnelid, J., Kastner, B., Alm, G. V. and Rönnblom, L. (2009), Regulation of the interferon-α production induced by RNA-containing immune complexes in plasmacytoid dendritic cells. Arthritis & Rheumatism, 60: 2418–2427. doi: 10.1002/art.24686
- Issue published online: 30 JUL 2009
- Article first published online: 30 JUL 2009
- Manuscript Accepted: 18 APR 2009
- Manuscript Received: 20 NOV 2008
- Dana Foundation
- Swedish Research Council
- Swedish Society of Medicine
- Swedish Rheumatism Foundation
- Uppsala University Hospital Development Foundation
- Agnes and Mac Rudberg Foundation
- Swedish Fund for Research Without Animal Experiments
- Nilsson Foundation
- King Gustaf V's 80-Year Foundation
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.
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.
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.
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.