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Neuroimmunomodulation. 2007;14(3-4):168-74. Epub 2007 Dec 5.

Modulation by astrocytes of microglial cell-mediated neuroinflammation: effect on the activation of microglial signaling pathways.

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  • 1Department of Neurology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.

Abstract

The strong inflammatory response observed in neurodegenerative diseases can depend on the impairment of the endogenous control of microglial activation, triggering the release of potentially detrimental factors such as cytokines, nitric oxide (NO) and superoxide anion (O(2)(-)). Our aim was to study the activation of microglial cells and the transduction pathways involved in their modulation by IL-1beta and TNF-alpha. Microglial and mixed glial cell cultures from neonatal rats were exposed to IFN-gamma and/or IL-1beta and TNF-alpha. We analyzed NO secretion and the activation of ERK and STAT1. We found that astrocytes modulated microglial cell activation, decreasing production of NO. IFN-gamma induced an 18- to 25-fold increase in NO, associated to a 3- to 5-fold increase in ERK phosphorylation in microglial cultures. IL-1beta, but not TNF-alpha, inhibited IFN-gamma-induced production of NO in microglia by 87%. It also reduced IFN-gamma-induced phosphoERK (pERK) by 40%, without affecting phosphoSTAT1 (pSTAT1). In contrast, in microglial cultures exposed to media conditioned by astrocytes, IL-1beta did not inhibit pERK, whereas it reduced activation of STAT1. Inducible NO synthase expression induced by IFN-gamma in microglial cultures was reduced when the activation of ERK was prevented. We propose that IL-1beta modulates IFN-gamma-induced production of oxidative molecules through cross talk between STAT1 and MAPK pathways, regulating the amplitude and duration of microglial activation. Modulation of ERK was observed at 30 min, whereas inhibition of pSTAT was observed later (at 4 h), indicating that it was an early and transient phenomenon.

Copyright 2007 S. Karger AG, Basel.

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