Yawei Guo1, Sookja Kim Chung2, Chung-Wah Siu3, Shing-Cheong Kwan4, Philip Wing-Lok Ho3, Patrick Ka-Kit Yeung2, Koon-Ho Chan5. 1. University Department of Medicine, Queen Mary Hospital, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong; Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong; Research Center of Heart, Brain, Hormone and Healthy Aging, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong. 2. Department of Anatomy, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong. 3. University Department of Medicine, Queen Mary Hospital, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong; Research Center of Heart, Brain, Hormone and Healthy Aging, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong. 4. University Department of Medicine, Queen Mary Hospital, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong; Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong. 5. University Department of Medicine, Queen Mary Hospital, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong; Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong; Research Center of Heart, Brain, Hormone and Healthy Aging, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong. Electronic address: koonho@hkucc.hku.hk.
Abstract
BACKGROUND: Multiple sclerosis (MS) is a CNS inflammatory demyelinating disorder. T helper 1 (Th1) and T helper 17 (Th17) cells are important in MS immunopathogenesis. Level of endothelin-1 (ET-1), a potent vasoconstrictor, is increased in sera of MS patients. We studied the role of ET-1 in experimental allergic encephalomyelitis (EAE), a MS animal model. METHODS: EAE is induced in transgenic mice overexpressing endothelial ET-1 (TET-1), transgenic mice overexpressing astrocytic ET-1 (GET-1) and non-transgenic (NTg) mice by immunization with myelin oligodendrocyte glycoprotein (MOG)35-55 peptide. EAE scores, spinal cord histology, serum proinflammatory cytokines levels, and proinflammatory cytokines production from splenocytes of ET-1 transgenic and NTg mice with EAE were studied. RESULTS: ET-1 transgenic mice developed more severe EAE than NTg with increased inflammation and demyelination in spinal cord. The mean maximum EAE scores for GET-1, TET-1 and NTg mice with EAE were 4.84, 4.31 and 4.05 respectively (p<0.05). Serum levels of IL-6, IL-17A, IFN-γ and TNF-α were higher in ET-1 transgenic than NTg mice with EAE (p<0.05) while serum IL-4 levels were similar. mRNA levels of IL-6, IL-17A, IFN-γ and TNF-α from cultured splenocytes were higher in ET-1-transgenic than NTg mice with EAE (p<0.05) while IL-4 mRNA levels were similar. Consistently, levels of IL-6, IL-17A, IFN-γ and TNF-α in culture media of splenocytes were higher in ET-1 transgenic than NTg mice with EAE (p<0.05) while IL-4 levels were similar. CONCLUSIONS: Mice with endothelial or astrocytic ET-1 overexpression developed more severe EAE with increased splenic lymphocyte production of Th1 and Th17 proinflammatory cytokines.
BACKGROUND:Multiple sclerosis (MS) is a CNS inflammatory demyelinating disorder. T helper 1 (Th1) and T helper 17 (Th17) cells are important in MS immunopathogenesis. Level of endothelin-1 (ET-1), a potent vasoconstrictor, is increased in sera of MSpatients. We studied the role of ET-1 in experimental allergic encephalomyelitis (EAE), a MS animal model. METHODS: EAE is induced in transgenic mice overexpressing endothelial ET-1 (TET-1), transgenic mice overexpressing astrocytic ET-1 (GET-1) and non-transgenic (NTg) mice by immunization with myelin oligodendrocyte glycoprotein (MOG)35-55 peptide. EAE scores, spinal cord histology, serum proinflammatory cytokines levels, and proinflammatory cytokines production from splenocytes of ET-1 transgenic and NTgmice with EAE were studied. RESULTS:ET-1transgenic mice developed more severe EAE than NTg with increased inflammation and demyelination in spinal cord. The mean maximum EAE scores for GET-1, TET-1 and NTgmice with EAE were 4.84, 4.31 and 4.05 respectively (p<0.05). Serum levels of IL-6, IL-17A, IFN-γ and TNF-α were higher in ET-1 transgenic than NTgmice with EAE (p<0.05) while serum IL-4 levels were similar. mRNA levels of IL-6, IL-17A, IFN-γ and TNF-α from cultured splenocytes were higher in ET-1-transgenic than NTgmice with EAE (p<0.05) while IL-4 mRNA levels were similar. Consistently, levels of IL-6, IL-17A, IFN-γ and TNF-α in culture media of splenocytes were higher in ET-1 transgenic than NTgmice with EAE (p<0.05) while IL-4 levels were similar. CONCLUSIONS:Mice with endothelial or astrocytic ET-1 overexpression developed more severe EAE with increased splenic lymphocyte production of Th1 and Th17 proinflammatory cytokines.