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This article is part of the supplement: 3rd World Congress of the Global Arthritis Research Network (GARN): International Arthritis Summit

Oral presentation

The role of IL-17 in the development of arthritis in mouse models

Y Iwakura, S Nakae, R Horai and S Saijo

Author Affiliations

Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan

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Arthritis Res Ther 2003, 5(Suppl 3):11  doi:10.1186/ar812


The electronic version of this article is the complete one and can be found online at:


Published:12 September 2003

©

Introduction

IL-17 is a T-cell-derived proinflammatory cytokine, which is suspected to be involved in the development of rheumatoid arthritis (RA) because this cytokine is found in sera and synovial tissues of RA patients. The pathogenic roles of IL-17 in the development of RA, however, still remain to be elucidated.

Objective

To elucidate the roles of IL-17 in the development of arthritis, we produced IL-17-deficient (IL-17-/-) mice, and examined the effect of deficiency on the development of arthritis in two etiologically different, spontaneous RA models, the HTLV-I transgenic mouse model and the IL-1 receptor antagonist (IL-1Ra)-deficient mouse model, as well as the type II collagen-induced arthritis model [1].

Methods

IL-17-/- mice were produced by replacing exon 1 and exon 2 of the il-17 gene with a neomycin resistance gene [2]. HTLV-I transgenic mice carrying the HTLV-I env-pX region and IL-1Ra-/- mice were produced as described elsewhere [3,4].

Results

Both HTLV-I transgenic mice and IL-1Ra-/- mice develop arthritis spontaneously due to autoimmunity caused by excess T-cell activation. The development of arthritis in HTLV-I transgenic mice was markedly suppressed in IL-17-/- mice, and that in IL-1Ra-/- mice was abolished completely (Fig. 1).

thumbnailFigure 1. Development of arthritis in IL-1Ra-/- is completely suppressed by the deficiency of IL-17.

Moreover, type II collagen-induced arthritis was markedly suppressed in IL-17-/- mice. We found that crosslinking of OX40 led to promote IL-17 production on CD4+ T cells, and OX40 expression was augmented in IL-1Ra-/- mice due to excess IL-1 signaling, resulting in the overproduction of IL-17. IL-17 was responsible for the priming of collagen-specific T cells and collagen-specific IgG2a production.

Conclusion

These observations suggest that IL-17 acts downstream to IL-1, and plays a crucial role in the development of arthritis by activating autoantigen-specific cellular and humoral immune responses.

Acknowledgement

This work was supported in part by a Grant-in-aid for Scientific Research on Priority Areas from MEXT, and the Ministry of Health, Labor and Welfare.

References

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    Proc Natl Acad Sci USA. 2003, 100:5986-5990. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  2. Nakae , et al.:

    Immunity. 2002, 17:375-387. PubMed Abstract | Publisher Full Text OpenURL

  3. Iwakura , et al.:

    Science. 1991, 253:1026-1028. PubMed Abstract OpenURL

  4. Horai , et al.:

    J Exp Med. 2000, 191:313-320. PubMed Abstract | Publisher Full Text OpenURL