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The protein tyrosine kinase inhibitor AG126 prevents the massive microglial cytokine induction by pneumococcal cell walls

Item Type:Article
Title:The protein tyrosine kinase inhibitor AG126 prevents the massive microglial cytokine induction by pneumococcal cell walls
Creators Name:Hanisch, U.K. and Prinz, M. and Angstwurm, K. and Haeusler, K.G. and Kann, O. and Kettenmann, H. and Weber, J.R.
Abstract:Central nervous system (CNS) infections caused by Streptococcus pneumoniae still have a disastrous outcome. Underlying immunological and CNS cellular events are largely enigmatic. We used pneumococcal cells walls (PCW) to investigate microglial responses as these cells are prominent sensors and effectors during neuropathological changes. PCW stimulation of mouse microglia in vitro evoked the release of the cyto- and chemokines, TNF-{alpha}, IL-6, IL-12, KC, MCP-1, MIP-1{alpha}, MIP-2 and RANTES as well as soluble TNF receptor II, a potential TNF-{alpha} antagonist. The release induction followed extremely steep dose-response relations, and short exposure periods (15 min) were already sufficient to trigger substantial responses. PCW signaling controlling the release depended on both p38 and p42/p44 (ERK2/ERK1) MAP kinase activities. The kinase inhibitor, tyrphostin AG126 prevented the PCW-inducible phosphorylation of p42/p44(MAPK), potently blocked cytokine release and drastically reduced the bioavailable TNF-{alpha}, since it only marginally affected the release of soluble TNF receptors. Moreover, in an in vivo model of pneumococcal meningitis, AG126 significantly attenuated the PCW-induced leukocyte influx to the cerebrospinal fluid. The findings imply that pneumococcal CNS infection can cause a rapid and massive microglial activation and that ERK/MAPK pathway(s) are potential targets for pharmacological interventions.
Keywords:Bacterial Meningitis, S. Pneumoniae, LPS, MAP Kinase
Source:European Journal of Immunology
ISSN:0014-2980
Publisher:Wiley (U.S.A.)
Volume:31
Number:7
Page Range:2104-2115
Date:July 2001
PubMed:View item in PubMed

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