IL-27 limits IL-2 production during Th1 differentiation.
Although the ability of IL-27 to promote T cell responses is well documented, the anti-inflammatory properties of this cytokine remain poorly understood. The current work demonstrates that during infection with Toxoplasma gondii, IL-27R-deficient mice generate aberrant IL-2 responses that are associated with the development of a lethal inflammatory disease. Because in vivo depletion of IL-2 prolongs the survival of infected IL-27R-/- mice, these data suggest that IL-27 curbs the development of immunopathology by limiting parasite-induced IL-2 production. Consistent with this hypothesis, IL-27R-/- CD4+ T cells produce more IL-2 than wild-type counterparts during in vitro differentiation, and when rIL-27 is introduced, it can suppress the expression of IL-2 mRNA and protein by the latter group. Additionally, these studies reveal that, like IL-27, IL-12 can inhibit IL-2 production, and although each employs distinct mechanisms, they can synergize to enhance the effect. In contrast, this property is not shared by closely related cytokines IL-6 and IL-23. Thus, while traditionally viewed as proinflammatory agents, the present findings establish that IL-27 and IL-12 cooperate to limit the availability of IL-2, a potent T cell growth and survival factor. Moreover, because the current studies demonstrate that both can induce expression of suppressor of cytokine signaling 3, a protein that tempers cytokine receptor signaling, they also suggest that IL-27 and IL-12 share additionally inhibitory properties.
Villarino
Alejandro V
AV
Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA.
Stumhofer
Jason S
JS
Saris
Christiaan J M
CJ
Kastelein
Robert A
RA
de Sauvage
Frederic J
FJ
Hunter
Christopher A
CA
D000818:Animals; D002454:Cell Differentiation; D005434:Flow Cytometry; D018664:Interleukin-12 / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000276:immunology; D007378:Interleukins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000166:cytology* / Q000276:immunology*; D014122:Toxoplasma; D014123:Toxoplasmosis / Q000276:immunology*
C486767:Il27 protein, mouse; D007376:Interleukin-2; D007378:Interleukins; D018664:Interleukin-12