The Journal of Experimental Medicine
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Published online January 2, 2007
doi:10.1084/jem.20061738
The Journal of Experimental Medicine, Vol. 204, No. 1, 161-170
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Kleinschek et al.
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ARTICLE

 IL-25 regulates Th17 function in autoimmune inflammation

Melanie A. Kleinschek1, Alexander M. Owyang1, Barbara Joyce-Shaikh1, Claire L. Langrish1, Yi Chen1, Daniel M. Gorman1, Wendy M. Blumenschein2, Terrill McClanahan2, Frank Brombacher3, Stephen D. Hurst1, Robert A. Kastelein1, and Daniel J. Cua1

1 Discovery Research and 2 Experimental Pathology and Pharmacology, Schering-Plough Biopharma, Palo Alto, CA 94304
3 University of Cape Town, Rondebosch 7701, South Africa

CORRESPONDENCE Daniel J. Cua: daniel.cua{at}spcorp.com

Interleukin (IL)-25 is a member of the IL-17 family of cytokines. However, unlike the other members of this family, IL-25 promotes T helper (Th) 2 responses. We now show that IL-25 also regulates the development of autoimmune inflammation mediated by IL-17–producing T cells. We have generated IL-25–deficient (il25–/–) mice and found that they are highly susceptible to experimental autoimmune encephalomyelitis (EAE). The accelerated disease in the il25–/– mice is associated with an increase of IL-23 in the periphery and a subsequent increase in the number of inflammatory IL-17–, IFN{gamma}-, and TNF-producing T cells that invade the central nervous system. Neutralization of IL-17 but not IFN{gamma} in il25–/– mice prevented EAE, suggesting that IL-17 is a major disease-promoting factor. IL-25 treatment at several time points during a relapse-remitting model or chronic model of EAE completely suppressed disease. IL-25 treatment induced elevated production of IL-13, which is required for suppression of Th17 responses by direct inhibition of IL-23, IL-1ß, and IL-6 expression in activated dendritic cells. Thus, IL-25 and IL-17, being members of the same cytokine family, play opposing roles in the pathogenesis of organ-specific autoimmunity.

Abbreviations used: CNS, central nervous system; DLN, draining lymph node; EAE, experimental autoimmune encephalomyelitis; HR, homologous recombination; MOG, myelin oligodendrocyte glycoprotein; PTX, pertussis toxin; rAdV, replication-deficient adenoviral vector.

M.A. Kleinschek and A.M. Owyang contributed equally to this paper.

C.L. Langrish's present address is Roche Bioscience, Palo Alto, CA 94304.

S.D. Hurst's present address is Genentech, South San Francisco, CA 94080.


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