Human fibroblasts exposed tovery-long-chain fatty acids exhibited increased mRNA expression of IL-1alpha and IL-1beta cytokines.Furthermore, expression of IL-6 and IL-8 cytokines in patient fibroblasts

Among several peroxisomal neurodegenerative disorders, the pseudoneonatal adrenoleukodystrophy(P-NALD) is characterized by the acyl-coenzymeAoxidase 1 (ACOX1) deficiency, which leadsto 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 usedtranscriptomic profiling and PCR array analyses to explore inflammatory gene expression in patientfibroblasts. Our results show the activation of IL-1 inflammatory pathway accompanied by theincreased secretion of two IL-1 target genes, IL-6 and IL-8 cytokines. Human fibroblasts exposed tovery-long-chain fatty acids exhibited increased mRNA expression of IL-1alpha and IL-1beta cytokines.Furthermore, expression of IL-6 and IL-8 cytokines in patient fibroblasts was down-regulated byMAPK, p38MAPK, and Jun Nterminal kinase inhibitors. Thus, the absence of acyl-coenzyme A oxidase 1 activity in PNALD fibroblasts triggers an inflammatory process, in which the IL-1 pathwayseems to be central. The use of specific kinase inhibitors may permit the modulation of the enhanced inflammatory status. Introduction In several peroxisomal disorders, the peroxisomal fatty acid beta-oxidation pathway is defective. This may be dueto the specific deficiency of an enzyme or transporter involved in peroxisomal beta-oxidation or the absence of thecomplete organelle resulting from a genetic defect in oneof the many genes required for proper peroxisome biogenesisand maintenance (1, 2). Pseudoneonatal adrenoleukodystrophy(P-NALD) (OMIM 264470) is a rare,neuroinflammatory, and a neurodegenerative peroxisomal disorder characterized by craniofacial dysmorphia,generalized hypotonia, hepatomegaly, infantile seizures,loss of motor achievements, and white matter demyelination(3– 6). P-NALD disease is due to acyl-coenzyme A(CoA) oxidase 1 (ACOX1) deficiency, which leads to aselective impairment of the peroxisomal fatty acid beta-oxidationpathway specifically affecting the oxidation ofvery-long-chain fatty acids