Induction of cyclooxygenase-2 in reactive glial cells by the CD40 pathway: relevance to amyotrophic lateral sclerosis

J Neurochem. 2004 Oct;91(2):404-12. doi: 10.1111/j.1471-4159.2004.02727.x.

Abstract

An inflammatory process in association with reactive gliosis has been suggested to play an important role in the pathogenesis of amyotrophic lateral sclerosis (ALS). One of the key findings is a marked increase in the level of cyclooxygenase-2 (COX-2), a therapeutic target of ALS. We investigated the expression of CD40 in the spinal cord of a transgenic mouse model of ALS (G93A mice), and its relevance to COX-2 upregulation. CD40 was predominantly expressed in neurons in normal spinal cord and upregulated in reactive glial cells in spinal cord injury. In the spinal cord of G93A mice, the expression of CD40 was increased in both reactive microglia and astrocytes, where COX-2 was especially increased. The level of COX-2 was upregulated in microglia and astrocytes by CD40 stimulation in vitro. CD40 stimulation in primary spinal cord cultures caused motor neuron loss that was protected by selective COX-2 inhibitor. These results suggest that CD40, which is upregulated in reactive glial cells in ALS, participates in motor neuron loss via induction of COX-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / enzymology
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Animals
  • CD40 Antigens / genetics
  • CD40 Antigens / metabolism*
  • CD40 Antigens / pharmacology
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology
  • Disease Models, Animal
  • Enzyme Induction / drug effects
  • Enzyme Induction / physiology
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / biosynthesis*
  • Isoenzymes / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Neuroglia / enzymology
  • Neuroglia / metabolism*
  • Neurons / cytology
  • Neurons / enzymology
  • Neurons / metabolism
  • Prostaglandin-Endoperoxide Synthases / biosynthesis*
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Signal Transduction / physiology
  • Spinal Cord Injuries / enzymology
  • Spinal Cord Injuries / metabolism
  • Superoxide Dismutase / genetics
  • Up-Regulation / drug effects
  • Up-Regulation / genetics

Substances

  • CD40 Antigens
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Isoenzymes
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • SOD1 G93A protein
  • Superoxide Dismutase