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Galactosylsphingosine (psychosine) ‐induced expression of cytokine‐mediated inducible nitric oxide synthases via AP‐1 and C/EBP: implications for Krabbe disease
Author(s) -
Giri Shailendra,
Jatana Manu,
Rattan Ramandeep,
Won JeSeong,
Singh Inderjit,
Singh Avtar K.
Publication year - 2002
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.01-0798com
Subject(s) - krabbe disease , proinflammatory cytokine , cytokine , nitric oxide synthase , nitric oxide , tumor necrosis factor alpha , biology , astrocyte , microbiology and biotechnology , chemistry , leukodystrophy , immunology , inflammation , medicine , endocrinology , central nervous system , disease
Globoid cell leukodystrophy (Krabbe disease) is characterized by the accumulation of a toxic metabolite, psychosine (galactosylsphingosine), which is a substrate for the deficient enzyme (galactocerebroside β‐galactosidase). This study underscores the possible role of psychosine in the effect of inducible nitric oxide synthase (iNOS) ‐derived NO in the pathophysiology of this demyelinating disease. For the first time, we provide evidence of the expression of iNOS in CNS of Krabbe patient and show that the iNOS‐expressing cells in the CNS were astrocytes. Psychosine potentiated the LPS‐induced production of proinflammatory cytokines (IL‐1β, IL‐6, and TNF‐α) in primary rat astrocytes and regulated the cytokine‐mediated production of NO in C 6 glioma and primary rat astrocyte. Psychosine induced cytokine‐mediated nuclear translocation of AP‐1 and C/EBP by potentiating the expression of Fra‐1 and C/EBP‐δ proteins. This suggests that psychosine maintained or sustained the cytokineprimed expression of iNOS by further potentiating the nuclear translocation of AP‐1 and C/EBP without modulating the cytokine‐mediated transcription activity of NF‐κB. This study hypothesizes that accumulated psychosine leads to production of cytokines and iNOS expression. The ensuing excessive production of NO and ONOO ‐ may play a role in pathogenesis of Krabbe disease.