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

Abstract

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-Δ12,14-PGJ2 (15d-PGJ2) in LPS-treated microglia. Two other anti-inflammatory cytokines, IL-10 and TGF-β, 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 γ (ciglitazone) mimicked the effect of PGE2 and 15d-PGJ2, and an EP2 antagonist (AH6809) and a peroxisome proliferator-activated receptor γ 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.