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Interleukin-1 drives cerebrovascular inflammation via MAP kinase-independent pathways

Research output: Contribution to journalArticle

  • Peter Thornton
  • Barry W McColl
  • Laura Cooper
  • Nancy J Rothwell
  • Stuart M Allan

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Original languageEnglish
Pages (from-to)330-40
Number of pages11
JournalCurrent Neurovascular Research
Volume7
Issue number4
Publication statusPublished - 2010

Abstract

Cerebrovascular inflammation is triggered by diverse central nervous system (CNS) insults and contributes to disease pathogenesis. The pro-inflammatory cytokine interleukin (IL)-1 is central to this cerebrovascular inflammatory response and understanding the underlying signalling mechanisms of IL-1 actions in brain endothelium may provide therapeutic targets for disease intervention. For the first time, we compare the contributions of p38, JNK and ERK mitogen-activated protein (MAP) kinase and NF-kB pathways to IL-1-induced brain endothelial activation. In cultures of primary mouse brain endothelium and the rat brain endothelial GPNT cell line, interleukin-1β (IL-1β induced a rapid (within 5 minutes) and transient activation of p38 and JNK (but not ERK) MAP kinases. IL-1β also induced nuclear recruitment of nuclear factor (NF)-kB p65. IL-1β-induced brain endothelial expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 was insensitive to MAP kinase inhibitors. IL-1β-induced brain endothelial expression of ICAM-1 and VCAM-1 was inhibited (80-88 %) by the proteasome inhibitor MG132 or the antioxidant caffeic acid phenethyl ester (CAPE), effects suggested to be NF-kB-dependent. IL-1β-induced brain endothelial CXCL1 expression was partially inhibited by JNK MAP kinase or MG132 (62 or 56 %, respectively). However, CXCL1 secretion from brain endothelium was reduced (65 %) only by MG132, and not MAP kinase inhibitors. Similarly, IL-1β-induced neutrophil transendothelial migration was reduced (77-89 %) by MG132, but not MAP kinase inhibitors. In summary, we show that several key components of IL-1β-induced brain endothelial activation (CAM, CXCL1 expression or release and neutrophil transmigration) are largely independent of MAP kinase activity but are reduced by proteasome inhibition, possibly reflecting a requirement for NF-kB activity. Similar mechanisms may contribute to cerebrovascular inflammation in response to CNS injury.

    Research areas

  • Analysis of Variance, Animals, Antigens, CD31, Brain, Cell Movement, Cells, Cultured, Cycloheximide, Dose-Response Relationship, Drug, Drug Interactions, Endothelial Cells, Enzyme Inhibitors, Enzyme-Linked Immunosorbent Assay, Gene Expression Regulation, Enzymologic, Interleukin 1 Receptor Antagonist Protein, Interleukin-1, Male, Mice, Mice, Inbred C57BL, Mitogen-Activated Protein Kinase Kinases, NF-kappa B, Protein Synthesis Inhibitors, Rats, Signal Transduction

ID: 663029