In vitro and in vivo evidence for a role of the P2X7 receptor in the release of IL-1 beta in the murine brain.
The P2X(7) receptor (P2X(7)R) is a purinoceptor expressed predominantly by cells of immune origin, including microglial cells. P2X(7)R has a role in the release of biologically active proinflammatory cytokines such as IL-1 beta, IL-6 and TNFalpha. Here we demonstrate that when incubated with lipopolysaccharide (LPS), glial cells cultured from brain of P2X(7)R(-/-) mice produce less IL-1 beta compared to glial cells from brains of wild-type mice. This is not the case for TNFalpha and IL-6. Our results indicate a selective effect of the P2X7R gene deletion on release of IL-1 beta release but not of IL-6 and TNFalpha. In addition, we confirm that only microglial cells produce IL-1beta, and this release is dependent on P2X(7)R and ABC1 transporter. Because IL-1 beta is a key regulator of the brain cytokine network and P2X(7)R is an absolute requirement for IL-1 beta release, we further investigated whether response of brain cytokines to LPS in vivo was altered in P2X(7)R(-/-) mice compared to wild-type mice. IL-1 beta and TNFalpha mRNAs were less elevated in the brain of P2X(7)R(-/-) than in the brain of wild-type mice in response to systemic LPS. These results show that P2X7R plays a key role in the brain cytokine response to immune stimuli, which certainly applies also to cytokine-dependent alterations in brain functions including sickness behavior.
Mingam
Rozenn
R
PsyNuGen, INRA, UMR1286, CNRS, UMR5226, Université Victor Ségalen Bordeaux 2, 146 Rue Léo Saignat, 33077 Bordeaux, France.
De Smedt
Véronique
V
Amédée
Thierry
T
Bluthé
Rose-Marie
RM
Kelley
Keith W
KW
Dantzer
Robert
R
Layé
Sophie
S
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D007031:Hypothalamus / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D015213:Neuroimmunomodulation / Q000276:immunology*; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D058486:Receptors, Purinergic P2X7; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; C546469:P2rx7 protein, mouse; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D014409:Tumor Necrosis Factor-alpha