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IL-27 Blocks RORc Expression to Inhibit Lineage Commitment of Th17 Cells

Caroline Diveu^*, Mandy J. McGeachy^*, Katia Boniface^*, Jason S. Stumhofer, Manjiri Sathe, Barbara Joyce-Shaikh^*, Yi Chen^*, Cristina M. Tato^*, Terrill K. McClanahan, René de Waal Malefyt^*, Christopher A. Hunter, Daniel J. Cua^1,* and Robert A. Kastelein^1,*

^* Department of Immunology, Department of Experimental Pathology and Pharmacology Schering-Plough Biopharma, Palo Alto, CA 94304; and University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA 19104

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 TGFβ 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 RORt. 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Daniel J. Cua or Dr. Robert A. Kastelein, Department of Immunology, Schering-Plough Biopharma, 901 California Avenue, Palo Alto, CA 94304. E-mail addresses: daniel.cua{at}spcorp.com or rob.kastelein{at}spcrop.com

² Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; LN, lymph node; DLN, draining LN; DTH, delayed-type hypersensitivity; EBI3, EBV-induced gene 3; ROR, retinoid-related orphan receptor; WT, wild type.

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				M. El-behi, B. Ciric, S. Yu, G.-X. Zhang, D. C. Fitzgerald, and A. Rostami Differential Effect of IL-27 on Developing versus Committed Th17 Cells J. Immunol., October 15, 2009; 183(8): 4957 - 4967. [Abstract] [Full Text] [PDF]