title: The inflammatory response in acyl-CoA oxidase 1 deficiency (pseudoneonatal adrenoleukodystrophy).
abstract: Among several peroxisomal neurodegenerative disorders, the pseudoneonatal adrenoleukodystrophy (P-NALD) is characterized by the acyl-coenzyme A oxidase 1 (ACOX1) deficiency, which leads to the accumulation of very-long-chain fatty acids (VLCFA) and inflammatory demyelination. However, the components of this inflammatory process in P-NALD remain elusive. In this study, we used transcriptomic profiling and PCR array analyses to explore inflammatory gene expression in patient fibroblasts. Our results show the activation of IL-1 inflammatory pathway accompanied by the increased secretion of two IL-1 target genes, IL-6 and IL-8 cytokines. Human fibroblasts exposed to very-long-chain fatty acids exhibited increased mRNA expression of IL-1α and IL-1β cytokines. Furthermore, expression of IL-6 and IL-8 cytokines in patient fibroblasts was down-regulated by MAPK, p38MAPK, and Jun N-terminal kinase inhibitors. Thus, the absence of acyl-coenzyme A oxidase 1 activity in P-NALD fibroblasts triggers an inflammatory process, in which the IL-1 pathway seems to be central. The use of specific kinase inhibitors may permit the modulation of the enhanced inflammatory status.
authors.affiliation: Laboratoire de Biochimie du Peroxysome, Inflammation et Métabolisme Lipidique, Université de Bourgogne, Dijon F-21000, France.
authors.forename: H I
authors.initials: HI
authors.lastname: El Hajj
authors.forename: A
authors.initials: A
authors.lastname: Vluggens
authors.forename: P
authors.initials: P
authors.lastname: Andreoletti
authors.forename: K
authors.initials: K
authors.lastname: Ragot
authors.forename: S
authors.initials: S
authors.lastname: Mandard
authors.forename: S
authors.initials: S
authors.lastname: Kersten
authors.forename: H R
authors.initials: HR
authors.lastname: Waterham
authors.forename: G
authors.initials: G
authors.lastname: Lizard
authors.forename: R J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: J K
authors.initials: JK
authors.lastname: Reddy
authors.forename: Mustapha
authors.initials: M
authors.lastname: Cherkaoui-Malki
mesh_terms: D042962:Acyl-CoA Oxidase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D005227:Fatty Acids / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome
chemical_list: D005227:Fatty Acids; D018836:Inflammation Mediators; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D053495:Osteopontin; C017364:hexacosanoic acid; D042962:Acyl-CoA Oxidase