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Interleukin-13 Enhances Cyclooxygenase-2 Expression in Activated Rat Brain Microglia: Implications for Death of Activated Microglia¹

Myung-Soon Yang^*,, Kyung-Ae Ji^*,, Sae-Bom Jeon, Byung-Kwan Jin^,, Seung U. Kim^,,¶, Ilo Jou^*, and Eunhye Joe^2,*,,

^* Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea; Neuroscience Graduate Program, Ajou University School of Medicine, Suwon, Korea; Brain Disease Research Center, Ajou University School of Medicine, Suwon, Korea; Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Korea; and ^¶ Department of Neurology, University of British Columbia, Vancouver, Canada

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 PGE₂ and 15-deoxy-^12,14-PGJ₂ (15d-PGJ₂) in LPS-treated microglia. Two other anti-inflammatory cytokines, IL-10 and TGF-, neither induced microglial death nor enhanced COX-2 expression or PGE₂ or 15d-PGJ₂ 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 PGE₂ and 15d-PGJ₂ induced microglial death. Agonists of EP2 (butaprost) and peroxisome proliferator-activated receptor (ciglitazone) mimicked the effect of PGE₂ and 15d-PGJ₂, and an EP2 antagonist (AH6809) and a peroxisome proliferator-activated receptor 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, PGE₂ and 15d-PGJ₂, caused microglial death, which terminates brain inflammation.

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