Mechanisms underlying extracellular ATP-evoked interleukin-6 release in mouse microglial cell line, MG-5

J Neurochem. 2001 Sep;78(6):1339-49. doi: 10.1046/j.1471-4159.2001.00514.x.

Abstract

Microglia play various important roles in the CNS via the synthesis of cytokines. The ATP-evoked production of interleukin-6 (IL-6) and its intracellular signals were examined using a mouse microglial cell line, MG-5. ATP, but not its metabolites, produced IL-6 in a concentration-dependent manner. Although ATP activated two mitogen-activated protein kinases, i.e. p38 and extracellular signal-regulated protein kinase, only p38 was involved in the IL-6 induction. However, the activation of p38 was not sufficient for the IL-6 induction because 2'- and 3'-O-(4-benzoylbenzoyl) ATP, an agonist to P2X7 receptors, failed to produce IL-6 despite the fact that it activated p38. Unlike in other cytokines in microglial cells, P2Y rather than P2X7 receptors seem to have a major role in the IL-6 production by the cells. The ATP-evoked IL-6 production was attenuated by Gö6976, an inhibitor of Ca(2+)-dependent protein kinase C (PKC). The P2Y receptor responsible for these responses was insensitive to pertussis toxin (PTX) and was linked to phospholipase C. Taken together, ATP acting on PTX-insensitive P2Y receptors activates p38 and Ca(2+)-dependent PKC, thereby resulting in the mRNA expression and release of IL-6 in MG-5. This is a novel pathway for the induction of cytokines in microglia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / analogs & derivatives*
  • Adenosine Triphosphate / metabolism*
  • Adenosine Triphosphate / pharmacology
  • Animals
  • Calcium / physiology
  • Cell Line
  • Enzyme Activation / physiology
  • Extracellular Space / metabolism*
  • Gene Expression / drug effects
  • Gene Expression / physiology
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Interleukin-6 / pharmacology
  • Mice
  • Microglia / drug effects
  • Microglia / metabolism*
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphorylation
  • Protein Kinase C / physiology
  • Purinergic Agonists
  • Receptors, Purinergic P2 / physiology
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Interleukin-6
  • Purinergic Agonists
  • Receptors, Purinergic P2
  • 3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate
  • Adenosine Triphosphate
  • Protein Kinase C
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Calcium