Taizo Matsuki

IL-17 is a proinflammatory cytokine that activates T cells and other immune cells to produce a variety of cytokines, chemokines, and cell adhesion molecules. This cytokine is augmented in the sera and/or tissues of patients with contact dermatitis, asthma, and rheumatoid arthritis. We previously demonstrated that IL-17 is involved in the development of autoimmune arthritis and contact, delayed, and airway hypersensitivity in mice. As the expression of IL-17 is also augmented in multiple sclerosis, we examined the involvement of this cytokine in these diseases using IL-17(-/-) murine disease models. We found that the development of experimental autoimmune encephalomyelitis (EAE), the rodent model of multiple sclerosis, was significantly suppressed in IL-17(-/-) mice; these animals exhibited delayed onset, reduced maximum severity scores, ameliorated histological changes, and early recovery. T cell sensitization against myelin oligodendrocyte glycoprotein was reduced in IL-17(-/-) mice upon sensitization. The major producer of IL-17 upon treatment with myelin digodendrocyte glycopritein was CD4+ T cells rather than CD8+ T cells, and adoptive transfer of IL-17(-/-) CD4+ T cells inefficiently induced EAE in recipient mice. Notably, IL-17-producing T cells were increased in IFN-gamma(-/-) cells, while IFN-gamma-producing cells were increased in IL-17(-/-) cells, suggesting that IL-17 and IFN-gamma mutually regulate IFN-gamma and IL-17 production. These observations indicate that IL-17 rather than IFN-gamma plays a crucial role in the development of EAE.

IL-1 is a proinflammatory cytokine that plays important roles in inflammation. However, the role of this cytokine under physiological conditions is not known completely. In this paper, we analyzed the role of IL-1 in maintaining body weight because IL-1 receptor antagonist-deficient (IL-1Ra-/-) mice, in which excess IL-1 signaling may be induced, show a lean phenotype. Body fat accumulation was impaired in IL-1Ra-/- mice, but feeding behavior, expression of hypothalamic factors involved in feeding control, energy expenditure, and heat production were normal. When IL-1Ra-/- mice were treated with monosodium glutamate (MSG), which causes obesity in wild-type mice by ablating cells in the hypothalamic arcuate nucleus, they were resistant to obesity, indicating that excess IL-1 signaling antagonizes the effect of MSG-sensitive neuron deficiency. IL-1Ra-/- mice showed decreased weight gain when they were fed the same amount of food as wild-type mice, and lipid accumulation remained impaired even when they were fed a high-fat diet. Interestingly, serum insulin levels and lipase activity were low in IL-1Ra-/- mice, and the insulin levels were low in contrast to wild-type mice after MSG treatment. These observations suggest that IL-1 plays an important role in lipid metabolism by regulating insulin levels and lipase activity under physiological conditions.

OBJECTIVE: Interleukin (IL)-1 plays an important role in atherosclerosis. IL-1 receptor antagonist (IL-1Ra) is an endogenous inhibitor of IL-1. However, the role of IL-1Ra in the development of atherosclerosis is poorly understood. METHODS AND RESULTS: Mice that lacked IL-1Ra (IL-1Ra-/-) were crossed with apolipoprotein E-deficient (E-/-) mice and formation of atherosclerotic lesions was analyzed after 16 weeks or 32 weeks consumption of a normal chow diet. This study focused on the comparison of atherosclerotic lesion between IL-1Ra+/+/apoE-/- (n=12) and IL-1Ra(+/-)/apoE-/- mice (n=12), because of the significantly leaner phenotype in IL-1Ra-/-/apoE-/- mice compared with the others. Interestingly, atherosclerotic lesion size in IL-1Ra+/-/apoE-/- mice at age 16 weeks was significantly increased (30%) compared with IL-1Ra+/+/apoE-/- mice (P<0.05). At 32 weeks, the differences of lesion size between these mice failed to achieve statistical significance. However, immunostaining demonstrated an 86% (P<0.0001) increase in the MOMA-2-stained lesion area of IL-1Ra+/-/apoE-/- mice. In addition, alpha-actin staining in these lesions was significantly decreased (-15%) compared with those in IL-1Ra+/+/apoE-/- mice (P<0.05). CONCLUSIONS: These results suggest an important role of IL-1Ra in the suppression of lesion development during early atherogenesis and furthermore indicate its role in the modulation of plaque composition.

IL-1 is a pro-inflammatory cytokine that plays an important role in inflammation and host responses to infection. We have previously shown that imbalances in the IL-1 and IL-1R antagonist (IL-1Ra) system cause the development of inflammatory diseases. To explore the role of the IL-1/IL-1Ra system in autoimmune disease, we analyzed myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in mice bearing targeted disruptions of the IL-1alpha, IL-1beta, IL-1alpha and IL-1beta (IL-1) or IL-1Ra genes. IL-1alpha/beta double-deficient (IL-1-/-) mice exhibited significant resistance to EAE induction with a significant reduction in disease severity, while IL-1alpha-/- or IL-1beta-/- mice developed EAE in a manner similar to wild-type mice. IL-1Ra-/- mice also developed MOG-induced EAE normally with pertussis toxin (PTx) administration. In contrast to wild-type mice, however, these mice were highly susceptible to EAE induction in the absence of PTx administration. We found that both IFN-gamma and IL-17 production and proliferation were reduced in IL-1-/- T cells upon stimulation with MOG, while IFN-gamma, IL-17 and tumor necrosis factor-alpha production and proliferation were enhanced in IL-1Ra-/- T cells. These observations suggest that the IL-1/IL-1Ra system is crucial for auto-antigen-specific T cell induction and contributes to the development of EAE.

Hypothalamic neurons that contain the neuropeptide orexin (hypocretin) play important roles in the regulation of sleep/wake. Here we analyze the in vivo and in vitro phenotype of mice lacking the GABA(B1) gene specifically in orexin neurons (oxGKO mice) and demonstrate that GABA(B) receptors on orexin neurons are essential in stabilizing and consolidating sleep/wake states. In oxGKO brain slices, we show that the absence of GABA(B) receptors decreases the sensitivity of orexin neurons to both excitatory and inhibitory inputs because of augmented GABA(A)-mediated inhibition that increases the membrane conductance and shunts postsynaptic currents in these neurons. This increase in GABA(A)-mediated inhibitory tone is apparently the result of an orexin receptor type 1-mediated activation of local GABAergic interneurons that project back onto orexin neurons. oxGKO mice exhibit severe fragmentation of sleep/wake states during both the light and dark periods, without showing an abnormality in total sleep time or signs of cataplexy. Thus, GABA(B) receptors on orexin neurons are crucial in the appropriate control of the orexinergic tone through sleep/wake states, thereby stabilizing the state switching mechanisms.