Endothelin-1 overexpression exacerbates experimental autoimmune encephalomyelitis

Abstract

Multiple sclerosis (MS) is a central nervous system 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 vasoconstrictor, is increased in sera of MS patients. We studied the role of ET-1 in experimental allergic encephalomyelitis (EAE), a MS animal model. EAE was induced in transgenic mice overexpressing endothelial ET-1 (TET-1), transgenic mice overexpressing astrocytic ET-1 (GET-1) and non-transgenic (NTg) mice by immunisation 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. 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 interleukin (IL)–6, IL-17A, interferon (IFN)–γ and tumour necrosis factor (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. We concluded that mice with endothelial or astrocytic ET-1 overexpression developed more severe EAE with increased splenic lymphocytes production of Th1 and Th17 proinflammatory cytokines.