Mechanisms underlying extracellular ATP-evoked interleukin-6 release in mouse microglial cell line, MG-5.
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.
Shigemoto-Mogami
Y
Y
Division of Pharmacology, National Institute of Health Sciences, Setagaya, Tokyo, Japan.
Koizumi
S
S
Tsuda
M
M
Ohsawa
K
K
Kohsaka
S
S
Inoue
K
K
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000502:physiology; D002460:Cell Line; D004789:Enzyme Activation / Q000502:physiology; D005110:Extracellular Space / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology; D058913:Purinergic Agonists; D018048:Receptors, Purinergic P2 / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D015850:Interleukin-6; D058913:Purinergic Agonists; D018048:Receptors, Purinergic P2; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium