J Korean Med Sci.  2006 Aug;21(4):733-738. 10.3346/jkms.2006.21.4.733.

Upregulation of Proinflammatory Cytokines in the Fetal Brain of the Gaucher Mouse

• Hong YB
• Kim EY
• Jung SC

• KMID: 2157830
• DOI: http://doi.org/10.3346/jkms.2006.21.4.733

Abstract

Gaucher disease is caused by a deficiency of glucocerebrosidase. Patients with Gaucher disease are divided into three major phenotypes: chronic nonneuronopathic, acute neuronopathic, and chronic neuronopathic, based on symptoms of the nervous system, the severity of symptoms, and the age of disease onset. The characteristics of patients with acute neuronopathic- and chronic neuronopathic-type Gaucher disease include oculomotor abnormalities, bulbar signs, limb rigidity, seizures and occasional choreoathetoid movements, and neuronal loss. However, the mechanisms leading to the neurodegeneration of this disorder remain unknown. To investigate brain dysfunction in Gaucher disease, we studied the possible role of inflammation in neurodegeneration during development of Gaucher disease in a mouse model. Elevated levels of the proinflammatory cytokines, IL-1alpha, IL-1beta, IL-6, and TNF-alpha, were detected in the fetal brains of Gaucher mice. Moreover, the levels of secreted nitric oxide and reactive oxygen species in the brains of Gaucher mice were higher than in wild-type mice. Thus, accumulated glucocerebroside or glucosylsphingosine, caused by glucocerebrosidase deficiency, may mediate brain inflammation in the Gaucher mouse via the elevation of proinflammatory cytokines, nitric oxide, and reactive oxygen species.

Keyword

Gaucher Disease; Glucosylceramidase; Glucocerebrosidase; Models, Animal; Mice; Brain; Cytokines; Nitric Oxide

MeSH Terms

Up-Regulation/genetics
Tumor Necrosis Factor-alpha/genetics/secretion
Reverse Transcriptase Polymerase Chain Reaction
Reactive Oxygen Species/metabolism
RNA, Messenger/genetics/metabolism
Nitric Oxide/metabolism
Microglia/cytology/metabolism
Mice, Knockout
Mice, Inbred ICR
Mice, Inbred C57BL
Mice
Interleukin-6/genetics/secretion
Interleukin-1/genetics/secretion
Inflammation/immunology
Glucosylceramidase/genetics
Gaucher Disease/*genetics/metabolism/pathology
Cytokines/*genetics/immunology/secretion
Cells, Cultured
Brain/embryology/*metabolism/pathology
Animals

Figure

• 

  Fig. 1 RT-PCR analysis of IL-1α, IL-1β, IL-6 and TNF-α mRNA expression in mouse brains (A) and of IL-6 and TNF-α mRNA expression in cultured microglia with or without 200 µM of CBE (conduritol B epoxide; see Materials and Methods) (B). Cytokines secreted from cultured microglia were analyzed (C): Open bar, untreated microglia; closed bar, microglia treated with 200 µM of CBE for 8 days. W-Cx, cerebral cortex of wild type mouse; G-Cx, cerebral cortex of Gaucher mouse; W-Bs, brainstem of wild type; G-Bs, brainstem of Gaucher mouse; W-Cbll, cerebellum of wild type; G-Cbll cerebellum of Gaucher mouse.

• 

  Fig. 2 NO release from cultured brain cells of cerebral cortex, brainstem and cerebellum. Open bars, NO levels from cells of wild type mice; closed bars, NO levels from cells of Gaucher mice. *p<0.01, †p<0.001 vs. wild type mice (by paired t tests).

• 

  Fig. 3 Detection of ROS with CM-H2DCFDA (see Materials and methods) in the microglial cells of cerebral cortex (A and D), brainstem (B and E) and cerebellum (C and F) from wild type mice (n=3, dotted line) and Gaucher mice (n=3, solid line). Upper panel, cells from day E19.5 embryos; lower panel, cells from day P1 neonates.

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