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研究生(外文):Huang, Wan Chen
論文名稱(外文):Part1: Superoxide anion-dependent Raf/MEK/ERK activation by PPARg agonists 15-deoxy-D12,14-prostaglandin J2, ciglitazone and GW251929 Part2: Interleukin-4 modulates lipopolysaccharide-mediated nitric oxide and interleukin-6 release via inhibition of
指導教授(外文):Lin, Wan Wan
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在本篇研究中,我們主要想探討三種結構不同的PPARg作用劑造成ERK活化的訊息傳遞路徑。在鼠肌纖維母細胞C2C12中,給予15d-PGJ2 ciglitazone以及GW251929會隨著時間及濃度的增加而增加ERK1/2的磷酸化作用,而同時MEK的磷酸化作用及Raf-1的活性也隨著藥物的刺激而活化。此三種PPARg作用劑所造成ERK的磷酸化作用並不會受PKC的抑制劑GF109203X及Ro31-8220抑制,也不會受PI3K的抑制劑wortmannin或Ras抑制劑FPTI影響。相反的,ERK的磷酸化作用可被MEK抑制劑PD98059,百日咳毒素pertussis toxin,及抗氧化劑所抑制。利用超微量化學發光儀偵測其產生自由基的能力,結果顯示三種作用劑都能造成超氧陰離子自由基產生,其作用程度15d-PGJ2>ciglitazone>GW251929,剛好與活化ERK的作用程度相類似。總結,在本篇研究中,我們發現三種PPARg的作用劑所造成ERK 的磷酸化作用是經由造成超氧陰離子自由基的產生及Raf/MEK/ERK的訊息傳遞路徑而來。
Interleukin-4 (IL-4)是ㄧ種具多功能的細胞激素,在發炎的過程中,可經由抑制發炎媒介物質的產生來抑制發炎反應的進行,而參與其中的分子機轉目前尚不清楚。在老鼠的巨噬細胞RAW 264.7中,我們發現IL-4能抑制LPS所引起NO及IL-6的產生,而這抑制作用會受PKC的抑制劑Ro31-8220,MEK的抑制劑PD98059以及p38 MAPK抑制劑SB203580所抑制,但不受PI3K的抑制劑wortmannin影響,顯示IL-4具有抑制LPS所引起PKC、ERK及p38 MAPK活性的能力。以上這些蛋白激脢在調節iNOS 及IL-6基因表現的訊息傳遞路徑中扮演重要角色。PI3K的活化當以Akt的磷酸化程度代表,在本實驗中發現同時給予LPS及IL-4的刺激對Akt的磷酸化有加成性作用。然而IL-4並不會影響LPS所引起NF-kB的活性,因為IL-4對於LPS所引起的IKK活化及IkB的分解並沒有影響。綜合以上結果:IL-4會經由抑制LPS活化PKC、ERK及p38 MAPK的活化作用,進而抑制NO及IL-6的產生。

Part I:
In this study, we examined the signaling pathways for ERK activation by three structurally different PPARg agonists. In murine C2C12 myoblasts, treatment with 15d-PGJ2, ciglitazone and GW251929 leads to ERK1/2 phosphorylation in a time- and concentration-dependent manner. Consistent with ERK phosphorylation, MEK phosphorylation as well as Raf-1 kinase activity are also accordingly stimulated. The ERK phosphorylation induced by PPARg agonists is not blocked by the PKC inhibitors GF109203X and Ro31-8220, the PI3K inhibitor wortmannin, neither the Ras inhibitor FPTI. On the contrary, the ERK phosphorylation by PPARg agonist is inhibited by the MEK inhibitor PD98059, pertussis toxin, and antioxidant. Chemiluminescence study reveals that these three PPARg agonists are able to induce superoxide anion production, with efficacy order similar to their action on ERK phosphorylation. Consistent with this notion, we also show that O2- donor DMNQ causes ERK phosphorylation. We conclude that the PPARg agonists, 15d-PGJ2, ciglitazone and GW251929 can induce ERK activation through superoxide anion production and the Raf/MEK/ERK signaling pathway.
Part II:
Interleukin-4 (IL-4) is a multifunctional cytokine that controls inflammatory processes by suppressing the production of proinflammatory mediators at the transcriptional level, but the molecular mechanisms involved have not been elucidated. In mouse RAW 264.7 macrophages, consistent with the inhibition of LPS-induced NO and IL-6 production by Ro 31-8220 (a PKC inhibitor), PD 98059 (an MEK inhibitor), and SB 203580 (a p38 MAPK inhibitor), but not by wortmannin (a PI3K inhibitor), we show that IL-4 functions to block LPS-increased PKC, ERK, and p38 MAPK activities. All these protein kinases are known to play crucial roles in signal transduction pathways leading to iNOS and IL-6 gene transcription. PI3K activity, as assessed from its downstream target of Akt phosphorylation, is increased by LPS and IL-4 in an additive manner. Furthermore, IL-4 does not influence LPS-induced NF-kB activity as evidenced from its ineffectiveness on LPS induction of IKK activation and IkB degradation. Taken together, we conclude that uncoupling of the upstream signals for LPS induction of PKC, ERK, and p38 MAPK activation contributes to IL-4 inhibition of LPS-induced NO and IL-6 production.


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