title: Activation of p38 Mitogen-Activated Protein Kinase in Gaucher's Disease.
abstract: Gaucher's disease is caused by defects in acid β-glucosidase 1 (GBA1) and has been also proposed as an inflammatory disease. GBA1 cleaves glucosylceramide to form ceramide, an established bioactive lipid, and defects in GBA1 lead to aberrant accumulation in glucosylceramide and insufficient formation of ceramide. We investigated if the pro-inflammatory kinase p38 is activated in Gaucher's disease, since ceramide has been proposed to suppress p38 activation. Three Gaucher's disease mouse models were employed, and p38 was found to be activated in lung and liver tissues of all Gaucher's disease mice. Most interestingly, neuronopathic Gaucher's disease type mice, but not non-neuronopathic ones, displayed significant activation of p38 and up-regulation of p38-inducible proinflammatory cytokines in brain tissues. In addition, all type of Gaucher's disease mice also showed increases in serum IL-6. As cellular signalling is believed to represent an in vivo inflammatory phenotype in Gaucher's disease, activation of p38 and possibly its-associated formation of proinflammatory cytokines were assessed in fibroblasts established from neuronopathic Gaucher's disease mice. In mouse Gaucher's disease cells, p38 activation and IL-6 formation by TNF-α treatment were enhanced as compared to those of wild type. Furthermore, human fibroblasts from Gaucher's disease patients also displayed increases in p38 activation and IL-6 formation as comparison to healthy counterpart. These results raise the potential that proinflammatory responses such as p38 activation and IL-6 formation are augmented in Gaucher's disease.
authors: Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan; Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors: Kazuyuki
authors: K
authors: Kitatani
authors: Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, United States of America.
authors: Masayuki
authors: M
authors: Wada
authors: Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors: David
authors: D
authors: Perry
authors: Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
authors: Toshinori
authors: T
authors: Usui
authors: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America; Departments of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
authors: Ying
authors: Y
authors: Sun
authors: Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, United States of America; Northport Veterans Affairs Hospital, Northport, New York, United States of America; Department of Medicine, Stony Brook University, Stony Brook, New York, United States of America.
authors: Lina M
authors: LM
authors: Obeid
authors: Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan; Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors: Nobuo
authors: N
authors: Yaegashi
authors: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America; Departments of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
authors: Gregory A
authors: GA
authors: Grabowski
authors: Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, United States of America; Department of Medicine, Stony Brook University, Stony Brook, New York, United States of America.
authors: Yusuf A
authors: YA
authors: Hannun
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005776:Gaucher Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D005962:Glucosylceramidase / Q000235:genetics / Q000378:metabolism; D005963:Glucosylceramides / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D005963:Glucosylceramides; C508600:IL6 protein, human; D015850:Interleukin-6; D048051:p38 Mitogen-Activated Protein Kinases; D005962:Glucosylceramidase