| 摘要: | 微膠細胞 (microglia)，是位於中樞神經系統 (central nervous system；CNS) 中先天的免疫細胞，被認為和神經元損傷最為相關。在活化態時，微膠細胞會促使自由基 (reactive oxygen species；ROS) 的生成和神經發炎而造成細胞毒性。漆黃素 (fisetin)，是由多種蔬果發現的一種類黃酮，具有抗氧化及抗發炎的特性。然而，利用漆黃素在微膠細胞中所造成的抗發炎細胞因子表現的作用目前瞭解並不多。在本篇論文中，我們研究經由漆黃素參與微膠細胞活化所造成促發炎反應的傳遞路徑。首先，經由不同濃度的漆黃素刺激會抑制微膠細胞中自由基和一氧化氮 (nitric oxide；NO)的生成，且也能抑制誘導型一氧化氮合成? (inducible nitric oxide synthase；iNOS) 和介白素-1β (interleukin-1β) mRNA的表現。此外，漆黃素也可調控抗發炎細胞因子的生成，如第一型血色素氧化酵素 (heme oxygenase-1；HO-1) 、內叉/異螺旋型轉錄因子P3 (forkhead box P3；FOXP3) 和細胞因子信號傳遞抑制體3 (suppressor of cytokine signaling-3；SOCS-3)，且利用第一型血色素氧化酵素的活化劑 (CoPP IX；HO-1 activator) 也可以抑制經LPS/IFN-γ所誘導的iNOS/NO生成。另外，漆黃素在不同濃度刺激下會增加p38和Akt磷酸化現象；而且漆黃素也能抑制LPS/IFN-γ刺激STAT-1活化而有隨時間增加的趨勢。根據我們的研究結果顯示，漆黃素可抑制微膠細胞中自由基的產生以及調節抗神經發炎因子的表現。而從動物實驗得知，漆黃素的神經保護作用是經由抑制LPS所誘發的微膠細胞活化而來。未來這些訊號傳遞路徑對於微膠細胞的活化可能可維持高動態平衡，並對於治療新興的抗發炎相關病症提供了新觀點。
Microglia, is the resident innate immune cell in the central nervous system (CNS). Microglia has been implicated as active contributor to neuronal damage, and provides an initial line defence against invading pathogens. In actived form, microglia cause reactive oxygen species (ROS) production, and neuroinflammation result to cytotoxicity. Fisetin, one of the major flavonol that found in a wide variety of fruits and vegetables, has anti-oxidant and anti-inflammatory activity. However, the effects of fisetin on neuroinflammatory responses in microglia were still poorly understood. In this study, we investigated the signaling pathways involved in anti-inflammatory responses caused by fisetin in microglia. First, fisetin caused concentration-dependent inhibits ROS and nitric oxide (NO) production. In addition, fisetin also inhibits iNOS and interleukin-1β (IL-1β) mRNA in a concentration-dependent manner. Moreover, fisetin also up-regulates the anti-inflammatory cytokine production, such as heme oxygenase-1 (HO-1), forkhead box P3 (FOXP3) and suppressor of cytokine signaling-3 (SOCS-3). HO-1 activator CoPP IX dramatically reversed LPS/IFN-γ-induced iNOS/NO production. Furthermore, fisetin increased p38 and Akt phosphorylation time-dependently. On the other hand, fisetin can effectively inhibit the LPS/IFN-γ stimulated signal transducer and activator of transcription-1 (STAT-1) activation of time-dependently. In a mouse model, fisetin showed significant anti-neuroinflammatory effects on microglial activation and motor behavior deficits. Our results indicate that fisetin potentially inhibits ROS generation, reduces iNOS/NO production and regulates anti- neuroinflammatory cytokine expression in microglia. With a future understanding of these signal transduction pathways, microglia activation may could enhance maintain inflammatory homeostasis, and this offers new insights for developing therapeutic approaches to treat novel anti-inflammatory-related disorders. |
