JAK2-STAT3 signaling pathway mediates thrombin-induced proinflammatory actions of microglia in vitro

J Neuroimmunol. 2008 Nov 15;204(1-2):118-25. doi: 10.1016/j.jneuroim.2008.07.004.

Abstract

The present study shows that JAK2-STAT3 inflammatory signaling mediates thrombin-stimulated microglia activation. In rat primary microglia, thrombin rapidly activated JAK2 and induced phosphorylation of STAT3. In addition, thrombin increased transcription of the inflammation-associated genes tumor necrosis factor (TNF)-alpha, inducible nitric oxide synthase (iNOS), production of TNF-alpha, NO and induced neurodegeneration of dopaminergic neurons in mesencephalic cultures. AG490, a JAK inhibitor, markedly reduced activation of JAK2 and STAT3 in thrombin-treated microglia. AG490 also inhibited thrombin-induced transcription and expression of TNF-alpha, iNOS and/or NO release, moreover rescued dopaminergic neurons. These results suggest that JAK2-STAT3 signaling pathway plays a critical role in mediating thrombin-induced activation of microglia and degeneration of dopaminergic neurons.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Animals, Newborn
  • CD11b Antigen / metabolism
  • Cells, Cultured
  • Coculture Techniques
  • Dopamine / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation, Enzymologic / drug effects
  • Janus Kinase 2 / metabolism*
  • Mesencephalon / cytology
  • Microglia / drug effects*
  • Nerve Degeneration / chemically induced
  • Neurons / drug effects
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism
  • RNA, Messenger
  • Rats
  • Rats, Sprague-Dawley
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / drug effects*
  • Thrombin / pharmacology*
  • Time Factors
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • Tyrphostins / pharmacology

Substances

  • CD11b Antigen
  • Enzyme Inhibitors
  • RNA, Messenger
  • STAT3 Transcription Factor
  • Stat3 protein, rat
  • Tumor Necrosis Factor-alpha
  • Tyrphostins
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • Nitric Oxide
  • Nitric Oxide Synthase Type II
  • Jak2 protein, rat
  • Janus Kinase 2
  • Thrombin
  • Dopamine