Suppression of manganese-dependent production of nitric oxide in astrocytes: implications for therapeutic modulation of glial-derived inflammatory mediators

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Title: Suppression of manganese-dependent production of nitric oxide in astrocytes: implications for therapeutic modulation of glial-derived inflammatory mediators
Author: Wright, Tyler T.
Abstract: Primary cultured astrocytes were treated with Mn in the absence and presence of proinflammatory cytokines to determine their effect upon stimulation of nitric oxide (NO ) production . Treatments of manganese and cytokines raised NO production to intermediate levels , whereas combined treatment raised NO creation to much greater levels . Furthermore , this combined treatment differed from control only in its ability to elevate cellular NO levels at 24 hours , but not at earlier time points . Combined exposure in astrocytes derived from mice lacking the nos2 gene prevented any increase in production of NO . Thus , manganese and cytokines enhance NO production through activation of the nos2 gene . Additionally , pharmacologic ligands of the peroxisome proliferator -activated receptor gamma (PPAR ? ) were used to test the role of this orphan nuclear receptor in modulating Mn -dependent production of NO . The agonist , 1 ,1 -Bis (3 ? -indolyl ) -1 - (p -trifluormethylphenyl ) methane (cDIM1 ) diminished NO in a dose -dependent manner , whereas addition of the PPAR ? antagonist , GW 9662 , amplified cellular NO production , also in a dose -dependent fashion . Moreover , it was observed that NO production was both attenuated and augmented at similar rates , suggesting the agonist and antagonist work through similar mechanisms . To clarify the means by which NO levels are manipulated by PPAR ? , we measured activation levels of the transcription factor NF - ?B , a primary factor resulting in expression of NOS2 . We found that NF - ?B was slightly activated in cells treated solely with manganese or cytokines , whereas cells treated with both manganese and cytokines showed the highest levels of activation . Also , we found that these ligands function through an NF - ?B dependent mechanism . Treatment of cDIM1 to astrocytes already treated with manganese and cytokines caused decreased activation of NF - ?B , while addition of GW9662 to similarly treated cells resulted in increased activation of NF - ?B . While these compounds were effective at manipulating induction of the nos2 gene , they had no effect on induction of guanosine tri -phosphate cyclohydrolase (GTPCH ) the rate limiting enzyme for the production of tetrahydrobiopterin (BH4 ) , a cofactor essential to the conversion of arginine to NO , Thus , these novel PPAR ? ligands can influence manganese - and cytokine -induced production of NO by an NF - ?B dependent mechanism .
URI: http : / /hdl .handle .net /1969 .1 /ETD -TAMU -1045
Date: 2009-05-15

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Suppression of manganese-dependent production of nitric oxide in astrocytes: implications for therapeutic modulation of glial-derived inflammatory mediators. Available electronically from http : / /hdl .handle .net /1969 .1 /ETD -TAMU -1045 .

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