IL-25 regulates Th17 function in autoimmune inflammation.
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-, IFNgamma-, and TNF-producing T cells that invade the central nervous system. Neutralization of IL-17 but not IFNgamma 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-1beta, 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.
Kleinschek
Melanie A
MA
Discovery Research, Schering-Plough Biopharma, Palo Alto, CA 94304, USA.
Owyang
Alexander M
AM
Joyce-Shaikh
Barbara
B
Langrish
Claire L
CL
Chen
Yi
Y
Gorman
Daniel M
DM
Blumenschein
Wendy M
WM
McClanahan
Terrill
T
Brombacher
Frank
F
Hurst
Stephen D
SD
Kastelein
Robert A
RA
Cua
Daniel J
DJ
D000818:Animals; D015551:Autoimmunity; D001483:Base Sequence; D002490:Central Nervous System / Q000276:immunology; D004247:DNA / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control; D005260:Female; D007249:Inflammation / Q000209:etiology / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000378:metabolism*; D007378:Interleukins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology
D020381:Interleukin-17; D007378:Interleukins; C442281:Mydgf protein, mouse; D007371:Interferon-gamma; D004247:DNA