IL-27 blocks RORc expression to inhibit lineage commitment of Th17 cells.
IL-27 is secreted by APCs in response to inflammatory stimuli and exerts a proinflammatory Th1-enhancing activity but also has significant anti-inflammatory functions. We examined the molecular mechanism by which IL-27 regulates TGFbeta plus IL-6- or IL-23-dependent Th17 development in the mouse and human systems. IL-27 inhibited the production of IL-17A and IL-17F in naive T cells by suppressing, in a STAT1-dependent manner, the expression of the Th17-specific transcription factor RORgamma t. The in vivo significance of the role of IL-27 was addressed in delayed-type hypersensitivity response and experimental autoimmune encephalomyelitis (EAE). By generating mice deficient for the p28 subunit of IL-27, we showed that IL-27 regulated the severity of delayed-type hypersensitivity response and EAE through its effects on Th17 cells. Furthermore, up-regulation of IL-10 in the CNS, which usually occurs late after EAE onset and plays a role in the resolution of the disease, was notably absent in IL-27p28(-/-) mice. These results show that IL-27 acts as a negative regulator of the developing IL-17A response in vivo, suggesting a potential therapeutic role for IL-27 in autoimmune diseases.
Diveu
Caroline
C
Department of Immunology, Schering-Plough Biopharma, Palo Alto, CA 94304, USA.
McGeachy
Mandy J
MJ
Boniface
Katia
K
Stumhofer
Jason S
JS
Sathe
Manjiri
M
Joyce-Shaikh
Barbara
B
Chen
Yi
Y
Tato
Cristina M
CM
McClanahan
Terrill K
TK
de Waal Malefyt
René
R
Hunter
Christopher A
CA
Cua
Daniel J
DJ
Kastelein
Robert A
RA
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation / Q000276:immunology; D020022:Genetic Predisposition to Disease; D006131:Growth Inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007378:Interleukins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D021122:Protein Subunits / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D011988:Receptors, Thyroid Hormone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
D006131:Growth Inhibitors; C486767:Il27 protein, mouse; D020381:Interleukin-17; D007378:Interleukins; C464565:MYDGF protein, human; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D021122:Protein Subunits; C539900:RORC protein, human; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; C539901:Rorc protein, mouse