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Inhibition of ERK MAPK Suppresses IL-23- and IL-1-Driven IL-17 Production and Attenuates Autoimmune Disease¹

Corinna F. Brereton^*, Caroline E. Sutton^*, Stephen J. Lalor^*, Ed C. Lavelle and Kingston H. G. Mills^2,*

^* Immune Regulation Research Group and Adjuvant Research Group, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland

IL-17-producing CD4⁺ T (Th17) cells are pathogenic in many autoimmune diseases. The induction and expansion of Th17 cells is directed by cytokines, including IL-23 and IL-1β, produced by innate immune cells through activation of pathogen recognition receptors. The NF-B and IFN regulatory factor families of transcriptional factors mediate IL-12 production; however, distinct signaling pathways appear to be required for IL-23 production. In this study, we show that inhibition of ERK MAPK suppressed IL-23 and IL-1β production by dendritic cells stimulated with TLR or dectin-1 agonists but did not affect IL-12p70 production. Furthermore, an ERK inhibitor suppressed the ability of Ag-pulsed TLR-activated dendritic cells to induce Ag-specific Th17 cells in vivo, but interestingly also inhibited the induction of Th1 cells. Treatment with an ERK inhibitor attenuated experimental autoimmune encephalomyelitis (EAE), when administered either at the induction phase of acute EAE or during remission in the relapsing-remitting EAE model. This was associated with significant suppression of autoantigen-specific Th17 and Th1 responses. The suppressive effect of the ERK inhibitor on attenuation of EAE was reversed by administration of IL-1β and IL-23. Our findings suggest that ERK MAPK plays a critical and hitherto undescribed role in activating innate production of IL-23 and IL-1β, which promote pathogenic T cell responses, and therefore represents an important target for therapeutic intervention against 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 This work was supported by Science Foundation Ireland.

² Address correspondence and reprint requests to Dr. Kingston H. G. Mills, School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland.

³ Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; IRF, IFN regulatory factor; DC, dendritic cell; EAU, experimental autoimmune uveitis; KLH, keyhole limpet hemocyanin; MOG, myelin oligodendrocyte glycoprotein; MTB, Mycobacteria tuberculosis; PLP, proteolipid protein; PT, pertussis toxin.