Abstract
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.
MeSH terms
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Animals
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cell Lineage / genetics
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Cell Lineage / immunology*
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Cells, Cultured
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Encephalomyelitis, Autoimmune, Experimental / genetics
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Gene Expression Regulation / immunology
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Genetic Predisposition to Disease
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Growth Inhibitors / deficiency
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Growth Inhibitors / genetics
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Growth Inhibitors / physiology*
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Humans
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Interleukin-17 / antagonists & inhibitors*
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Interleukin-17 / biosynthesis
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Interleukins / deficiency
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Interleukins / genetics
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Interleukins / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Nuclear Receptor Subfamily 1, Group F, Member 3
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Protein Subunits / deficiency
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Protein Subunits / genetics
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Protein Subunits / physiology
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Receptors, Retinoic Acid / antagonists & inhibitors*
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Receptors, Retinoic Acid / biosynthesis
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Receptors, Retinoic Acid / genetics
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Receptors, Thyroid Hormone / antagonists & inhibitors*
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Receptors, Thyroid Hormone / biosynthesis
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Receptors, Thyroid Hormone / genetics
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T-Lymphocytes, Helper-Inducer / immunology*
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T-Lymphocytes, Helper-Inducer / metabolism
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T-Lymphocytes, Helper-Inducer / pathology
Substances
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Growth Inhibitors
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Il27 protein, mouse
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Interleukin-17
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Interleukins
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MYDGF protein, human
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Nuclear Receptor Subfamily 1, Group F, Member 3
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Protein Subunits
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RORC protein, human
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Receptors, Retinoic Acid
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Receptors, Thyroid Hormone
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Rorc protein, mouse