Interleukin-17 as a molecular target in immune-mediated arthritis: Immunoregulatory properties of genetically modified murine dendritic cells that secrete interleukin-4
Version of Record online: 28 DEC 2006
Copyright © 2006 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 56, Issue 1, pages 89–100, January 2007
How to Cite
Sarkar, S., Tesmer, L. A., Hindnavis, V., Endres, J. L. and Fox, D. A. (2007), Interleukin-17 as a molecular target in immune-mediated arthritis: Immunoregulatory properties of genetically modified murine dendritic cells that secrete interleukin-4. Arthritis & Rheumatism, 56: 89–100. doi: 10.1002/art.22311
- Issue online: 2 JAN 2007
- Version of Record online: 28 DEC 2006
- Manuscript Accepted: 29 SEP 2006
- Manuscript Received: 25 APR 2006
- Arthritis Foundation
- NIH. Grant Number: AR-048310
Our previous studies have shown that murine dendritic cells (DCs) genetically modified to express interleukin-4 (IL-4) reduce the incidence and severity of murine collagen-induced arthritis. The present studies were performed to assess the immunoregulatory mechanisms underlying this response, by assessing the effects of IL-4 DCs on cytokine production by subsets of T helper cells.
Male DBA mice ages 6–8 weeks old were immunized with type II collagen. Splenic T cells obtained during the initiation phase and the end stage of arthritis were cultured with IL-4 DCs or untransduced DCs in the presence of collagen rechallenge. Interferon-γ (IFNγ) and IL-17 responses were measured. Antibodies to IL-4, IL-12, and IL-23, and recombinant IL-4, IL-12, and IL-23 were used to further study the regulation of T cell cytokine production by IL-4 DCs.
Splenic T cells obtained during the initiation phase of arthritis produced less IL-17 when cultured in the presence of IL-4 DCs, despite their production of increased quantities of other proinflammatory cytokines (IFNγ and tumor necrosis factor). T cell IL-17 production after collagen rechallenge was not inhibited by a lack of IL-23, since IL-4–mediated suppression of IL-17 was not reconstituted by IL-23, an otherwise potent inducer of IL-17 production by T cells. Although IL-4 DCs can produce increased quantities of IL-12 and IFNγ, suppression of IL-17 production by IL-4 DCs was independent of both. While IL-17 production by T cells obtained during the initiation phase of arthritis was regulated by IL-4 DCs, IL-17 production by T cells obtained during end-stage arthritis was not altered.
Our data suggest that IL-4 DCs exert a therapeutic effect on collagen-induced arthritis by targeting IL-17. IL-17 suppression by IL-4 DCs is robust and is not reversed by IL-23. Timing might be important in IL-17–targeted therapy, since IL-17 production by T cells obtained during end-stage arthritis did not respond to suppression by IL-4 DCs.