Early administration of IL-12 suppresses EAE through induction of interferon-g Bruno Gran a, * , Niansheng Chu a , Guang-Xian Zhang a , Shuo Yu a , Yonghai Li a , Xiao-Han Chen b , Malek Kamoun c , Abdolmohamad Rostami a a Department of Neurology, Thomas Jefferson University, 300 Hospital for Neuroscience, 900 Walnut Street, Philadelphia, PA 19107, United States b Department of Neurosurgery, University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104, United States c Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, HUP 7.020 Founders, 3400 Spruce Street, Philadelphia, PA 19104, United States Received 3 June 2004; received in revised form 22 July 2004; accepted 23 July 2004 Abstract Recent findings have shown that IL-12, a key inducer of Th1 cell development, is not required in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) as severe CNS inflammatory demyelination can develop in the absence of IL-12 or IL-12 responsiveness. These data raised the possibility of an immunomodulatory action of IL-12 in this disease model. We show here that IL-12 suppresses MOG35–55-induced EAE in the C57BL/6 mouse when administered during the early induction phase of the disease. The inhibitory effect is interferon-g-(IFN-g)-dependent, as clearly shown by lack of suppression in IFN-g-deficient mice, and is also accompanied by inhibition of mRNA expression of the proinflammatory cytokine IL-17. D 2004 Elsevier B.V. All rights reserved. Keywords: EAE; Cytokines; Autoimmunity; Rodent; Transgenic/Knockout 1. Introduction Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease that serves as a model for multiple sclerosis, an inflammatory demyelinating disease of the central nervous system (Steinman, 1999). IL-12 is a heterodimeric cytokine that is crucial in the development of T helper 1 cells, which produce high levels of interferon- gamma (IFN-g) and are thought to initiate an autoimmune attack directed against CNS myelin in EAE and MS (Trinchieri et al., 2003). IL-12 is comprised of an IL- 12p35 and an IL-12p40 subunit that are produced and secreted as bioactive heterodimers (IL-12p70) by antigen presenting cells (APC) (Ma and Trinchieri, 2001; Trinchieri et al., 2003). Until recently, IL-12 was considered a key factor in the induction of EAE. This was based on the observation of increased severity of adoptive transfer EAE when T cells are activated in vitro in the presence of IL-12 and suppression of disease by administration of neutralizing antibodies (Constantinescu et al., 1998; Leonard et al., 1995). In addition, administration of IL-12 was shown to exacerbate disease relapses or even induce relapses in monophasic EAE (Constantinescu et al., 1998; Smith et al., 1997). It has recently been shown that the IL-12-related cytokine IL-23, a heterodimer of IL-12p40 and a recently described IL-23p19 subunit, is more critical for EAE induction, whereas IL-12 is not required (Cua et al., 2003). In fact, IL-12p35-deficient mice retain EAE suscept- ibility (Becher et al., 2002; Gran et al., 2002), whereas IL- 23p19-deficient mice are completely resistant (Cua et al., 2003). The observation of severe EAE in mice deficient for either IL-12 (IL-12p35À/À) or the beta2 subunit of the IL- 12 receptor (IL-12Rh2À/À), which lack responsiveness to IL-12 but maintain responsiveness to IL-23, suggested a modulatory role for IL-12 (Zhang et al., 2003a). In this 0165-5728/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2004.07.019 * Corresponding author. Tel.: +1 215 955 8951; fax: +1 215 503 5848. E-mail address: bruno.gran@jefferson.edu (B. Gran). Journal of Neuroimmunology 156 (2004) 123 – 131 www.elsevier.com/locate/jneuroim