| First Author | Lalor SJ | Year | 2011 |
| Journal | J Immunol | Volume | 186 |
| Issue | 10 | Pages | 5738-48 |
| PubMed ID | 21471445 | Mgi Jnum | J:173098 |
| Mgi Id | MGI:5009731 | Doi | 10.4049/jimmunol.1003597 |
| Citation | Lalor SJ, et al. (2011) Caspase-1-processed cytokines IL-1beta and IL-18 promote IL-17 production by gammadelta and CD4 T cells that mediate autoimmunity. J Immunol 186(10):5738-48 |
| abstractText | IL-1beta plays a critical role in promoting IL-17 production by gammadelta and CD4 T cells. However, IL-1-targeted drugs, although effective against autoinflammatory diseases, are less effective against autoimmune diseases. Conversely, gain-of-function mutations in the NLRP3 inflammasome complex are associated with enhanced IL-1beta and IL-18 production and Th17 responses. In this study, we examined the role of caspase-1-processed cytokines in IL-17 production and in induction of experimental autoimmune encephalomyelitis (EAE). Killed Mycobacterium tuberculosis, the immunostimulatory component in CFA used for inducing EAE, stimulated IL-1beta and IL-18 production by dendritic cells through activation of the inflammasome complex and caspase-1. Dendritic cells stimulated with M. tuberculosis and myelin oligodendrocyte glycoprotein promoted IL-17 production by T cells and induced EAE following transfer to naive mice, and this was suppressed by a caspase-1 inhibitor and reversed by administration of IL-1beta or IL-18. Direct injection of the caspase-1 inhibitor suppressed IL-17 production by CD4 T cells and gammadelta T cells in vivo and attenuated the clinical signs of EAE. gammadelta T cells expressed high levels of IL-18R and the combination of IL-18 and IL-23, as with IL-1beta and IL-23, stimulated IL-17 production by gammadelta T cells, but also from CD4 T cells, in the absence of TCR engagement. Our findings demonstrate that caspase-1-processed cytokines IL-1beta and IL-18 not only promote autoimmunity by stimulating innate IL-17 production by T cells but also reveal redundancy in the functions of IL-1beta and IL-18, suggesting that caspase-1 or the inflammasome may be an important drug target for autoimmune diseases. |
