Cytokine-induced expression of type II nitric oxide synthase in astrocytes is downregulated by ATP and glutamate

✍ Scribed by Sean Murphy; Hsin Lee Lin; Song Kyu Park

• Publisher: John Wiley and Sons
• Year: 1995
• Tongue: English
• Weight: 652 KB
• Volume: 15
• Category: Article
• ISSN: 0894-1491
• DOI: 10.1002/glia.440150109

✦ Synopsis

Combinations of cytokines andor phorbol ester induce expression of Type I1 nitric oxide synthase (NOS) mRNA in astrocyte cultures via protein kinase mediated pathways (Simmons and Murphy: GLIA 11:227,1994; Feinstein et al.: J Neurochem 62:811, 1994). Agonists that activate receptors linked to protein kinases did not reproduce this effect of cytokines in astrocytes. On the contrary, ATP and glutamate treatment of astrocytes prior to a combination of interleukin-lp and interferon-y markedly reduced (30-50%) subsequent NOS mRNA expression. The effect was not seen if treatment coincided with or followed cytokine activation, suggesting that ATP and glutamate were not destabilizing NOS mRNA. The effects of ATP and glutamate were additive and could be mimicked by selective receptor agonists, but were insensitive to a specific inhibitor of protein kinase C. The inhibition of cytokine-induced NOS mRNA expression caused by these agents was not the result of interference with the activatiodtranslocation of nuclear factor-& by interleukin-lp. These results suggest that exposure of astrocytes to ATP and glutamate, both of which increase markedly in a variety of neuropathologies, could modulate the subsequent responsiveness of these cells to NOS-inducing stimuli. As such, this may be an important regulatory mechanism in the expression of Type I1 NOS in vivo.