Interleukin-13 enhances cyclooxygenase-2 expression in activated rat brain microglia: implications for death of activated microglia.
Brain inflammation has recently attracted widespread interest because it is a risk factor for the onset and progression of brain diseases. In this study, we report that cyclooxygenase-2 (COX-2) plays a key role in the resolution of brain inflammation by inducing the death of microglia. We previously reported that IL-13, an anti-inflammatory cytokine, induced the death of activated microglia. These results revealed that IL-13 significantly enhanced COX-2 expression and production of PGE(2) and 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) in LPS-treated microglia. Two other anti-inflammatory cytokines, IL-10 and TGF-beta, neither induced microglial death nor enhanced COX-2 expression or PGE(2) or 15d-PGJ(2) production. Therefore, we hypothesized that the effect of IL-13 on COX-2 expression may be linked to death of activated microglia. We found that COX-2 inhibitors (celecoxib and NS398) suppressed the death of microglia induced by a combination of LPS and IL-13 and that exogenous addition of PGE(2) and 15d-PGJ(2) induced microglial death. Agonists of EP2 (butaprost) and peroxisome proliferator-activated receptor gamma (ciglitazone) mimicked the effect of PGE(2) and 15d-PGJ(2), and an EP2 antagonist (AH6809) and a peroxisome proliferator-activated receptor gamma antagonist (GW9662) suppressed microglial death induced by LPS in combination with IL-13. In addition, IL-13 potentiated LPS-induced activation of JNK, and the JNK inhibitor SP600125 suppressed the enhancement of COX-2 expression and attenuated microglial death. Taken together, these results suggest that IL-13 enhanced COX-2 expression in LPS-treated microglia through the enhancement of JNK activation. Furthermore, COX-2 products, PGE(2) and 15d-PGJ(2), caused microglial death, which terminates brain inflammation.
Yang
Myung-Soon
MS
Department of Pharmacology, Ajou University School of Medicine, Suwon 442-721, Korea.
Ji
Kyung-Ae
KA
Jeon
Sae-Bom
SB
Jin
Byung-Kwan
BK
Kim
Seung U
SU
Jou
Ilo
I
Joe
Eunhye
E
D000818:Animals; D001921:Brain / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D016923:Cell Death / Q000276:immunology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000502:physiology; D016753:Interleukin-10 / Q000502:physiology; D018793:Interleukin-13 / Q000502:physiology*; D015847:Interleukin-4 / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D047495:PPAR gamma / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000502:physiology; D058307:Receptors, Prostaglandin E, EP2 Subtype; D016212:Transforming Growth Factor beta / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology*
D018793:Interleukin-13; D008070:Lipopolysaccharides; D047495:PPAR gamma; C545646:Ptger2 protein, rat; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D015847:Interleukin-4; D051546:Cyclooxygenase 2; D048031:JNK Mitogen-Activated Protein Kinases