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研究生： 林大鈞
Lin, Da-Chun
論文名稱： 巨噬細胞中PPARγ與發炎體活化的交互作用
Interplay between PPARγ and inflammasome activation in macrophages
指導教授： 蔡曜聲
Tsai, Yau-Sheng
學位類別： 碩士
Master
系所名稱： 醫學院 - 臨床醫學研究所
Institute of Clinical Medicine
論文出版年： 2013
畢業學年度： 101
語文別： 英文
論文頁數： 48
中文關鍵詞： 過氧化增生受體 、NLRP3 發炎體 、白細胞介素-1β 、凋亡蛋白酶-1
外文關鍵詞： PPARγ, NLRP3 inflammasome, IL-1β, caspase-1
相關次數： 點閱：133  下載：0 
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    • NLRP3發炎體(NLRP3 inflammasome)為一種表達於免疫細胞的聚合蛋白體，負責調控適應性免疫反應。當外來的微生物入侵或接受到死亡訊息時，細胞中的NLRP3、ASC和pro-caspase-1會相互連接形成NLRP3 inflammasome，接著切割caspase-1，促使發炎激素IL-1β釋放到細胞外並造成細胞死亡。因此，在許多發炎相關疾病的過程中，常發現到有不正常IL-1β的產生和發炎體過度活化的現象。過氧化增生受體(Peroxisome proliferator-activated receptors, PPARγ)是一種核激素受體(nuclear receptor protein)，負責調控脂肪細胞的分化與醣類的代謝，並且在巨噬細胞中也能夠發現PPARγ的存在。在許多的文獻指出，細胞能藉由PPARγ的活化抑制NF-κB的活化，進一步抑制發炎激素的生成，例如IL-1β。因此我們提出一個假說：PPARγ能夠抑制發炎體的活化。首先，我們在缺失PPARγ的巨噬細胞(PpargL/+)中給予LPS的刺激，我們發現發炎體活化的相關基因IL-1β、caspase-1和NLRP3的表現有明顯的上升。接著，我們利用PPARγ的促進劑Rosiglitazone刺激PPARγ的活化，從結果顯示PPARγ的活化能有效的抑制LPS和nigericin所造成caspase-1 和IL-β活化。並且，我們在PPARγ缺失的巨噬細胞(PpargC/- and PpargL/+)也發現，發炎體的活化程度相較於正常的細胞高，如此更能證明活化的PPARγ能夠抑制LPS和nigericin所造成發炎體的活化。除此之外，我們更發現PPARγ除了能夠抑制nigericin所刺激的發炎體的活化，它也能夠抑制結晶所誘導的發炎體活化。我們建立了一套轉染NLRP3發炎體的系統在HEK293T細胞，在這套人工的系統中，我們除了發現PPARγ的表現能夠抑制IL-1β的產生和發炎體的形成之外，更有趣的是，在免疫螢光染色和免疫沉澱的實驗中，我們發現PPARγ會與NLRP3相互連接，不論是在發炎體活化或不活化的巨噬細胞。在發炎體活化過程中，PPARγ的蛋白表現量有減少的情形。因此，我們進一步地利用NF-kB和proteasome抑制劑，確實能夠減緩在發炎體活化的過程中PPARγ的減少，如此也伴隨著發炎體的活化程度降低。但caspase-1的抑制劑則無法減緩這現象的發生。由上述結果證明，PPARγ是透過與NLRP3連接，進而抑制發炎體的活化。並且，在巨噬細胞發炎體活化的過程中，會造成PPARγ的表現減少。因此，從我們的研究結果發現了一個PPARγ抑制發炎反應的全新的功能，更重要的是，此結果提供了PPARγ促進劑在未來臨床上發炎體相關疾病治療的可行性。

    NLRP3 inflammasome, a multiprotein complex consisting of NLRP3, ASC and caspase-1, is expressed in immune cells and is a component for the innate immune system. Activators from microbe, stress and damage signals trigger inflammsome assembly to direct cleavage of caspase-1 for maturation and secretion of IL-1β and cell death. Thus, aberrant IL-1β production and inflammasome activation are important in diseases associated with dysregulated inflammatory responses. PPARγ, a nuclear hormone receptor, plays an important role in adipocyte differentiation and glucose homeostasis. PPARγ is also expressed in macrophages, and inhibits the expression of inflammatory cytokines, including IL-1β, by inhibition of NF-κB activation. Several studies showed an inverse correlation between PPARγ activation and IL-1β production. Thus we hypothesized that PPARγ attenuates inflammasome activation in macrophages. First, we found that expression of inflammasome components, IL-1β, caspase-1 and NLRP3, was increased in PPARγ-defective macrophages in response to LPS. Treatment of PPARγ agonist rosiglitazone attenuated cleavages of caspase-1 and IL-1β in LPS-primed nigericin-stimulated macrophages. Consistently, cleavages of caspase-1 and IL-1β were higher in macrophages from PPARγ-defective mice (PpargC/- and PpargL/+) than wild-type mice. Moreover, PPARγ activation during nigericin stimulation effectively attenuated inflammasome activation. In addition to nigericin, PPARγ activation also attenuated crystal-mediated NLRP3 inflammasome activation. We further set up an artificial NLRP3 inflammasome reconstituted system in HEK293T cells. We found that PPARγ also reduced IL-1β maturation and blocked inflammasome complex formation in reconstituted HEK293T cells. Interestingly, immunofluorescence staining and immunoprecipitaion showed that PPARγ was associated with NLRP3 in both basal and inflammasome activated states. Finally, we found that PPARγ was downregulated during inflammasome activation. Inhibition of NF-κB or proteasome, but not caspase-1, effectively attenuated PPARγ degradation. Prevention of PPARγ from degradation was associated with reduction of inflammasome activation. In conclusion, PPARγ attenuates NLRP3 inflammasome activation in macrophages, partly through its interaction with NLRP3. Upon inflammasome stimulation, PPARγ is then degraded to allow a full inflammasome activation. Our study demonstrates a novel function of PPARγ in attenuation of inflammatory response and provides a candidate for PPARγ agonist in the treatment of inflammasome-associated diseases.

    INTRODUCTION…………………………………………………………...1 Nod-like receptor………………………………………………………….1 NLRP3 inflammasome…………………………………………………....2 NLRP3 inflammasome activation………………………………………....3 NLRP3 inflammasome-associated disease………………………………..3 Inhibition of the inflammasome…………………………………………...4 Peroxisome proliferator-activated receptor γ……………………………...5 PPARγ in inflammation…………………………………………………...6 PPARγ downregulation by inflammatory signal………………………….7 Significance……………………………………………………………….8 MATERIALS AND METHODS……………………………………………9 Animal ……………………………………………………………………….9 Peritoneal macrophage isolation and treatment…………………………...9 RNA extaction…………………………………………………………….10 Reverse transcription and real-time PCR………………………………..10 Cellular protein extraction……………………………………………….11 Culture Medium protein extraction………………………………………12 Western blotting………………………………………………………….12 Immunofluorescence……………………………………………………..12 Immunoprecipitation………..……………………………………………13 Reconstituted inflammasome in HEK293T cells……………………….13 Data analysis……………………………………………………………..14 RESULTS…………………………………………………………………….15 Expression of inflammasome components was increased in LPS-primed PPARγ-defective macrophages…………………………………………..15 PPARγ attenuated inflammasome activation in macrophages…………...15 PPARγ activation during nigericin stimulation reduced inflammasome activation…………………………………………………………………16 PPARγ attenuated crystal-induced NLRP3 inflammasome activation in macrophages……………………………………………………………..17 PPARγ reduced IL-1β maturation and inflammasome complex formation in NLRP3 inflammasome-reconstituted HEK293T cells………………..17 PPARγ was associated with NLRP3……………………………………..19 PPARγ was downregulated during NLRP3 inflammasome activation…..19 PPARγ was degraded through NF-κB and proteasome, but not caspase-1 pathways during inflammasome activation……………………………...20 DISCUSSION………………………………………………………………...22 REFERENCES………………………………………………………………30 TABLE……………………………………………………………………….36 FIGURES…………………………………………………………………….37 Figure 1. Expression of inflammasome components were increased in LPS-stimulated PPARγ defective macrophages…………………………37 Figure 2. PPARγ attenuated inflammasome activation in macrophages...38 Figure 3. PPARγ activation attenuated nigericin-stimulated inflammasome activation………………………………………………………………..39 Figure 4. PPARγ attenuated NLRP3 inflammasome activation…………40 Figure 5. PPARγ reduced IL-1β maturation in NLRP3 inflammasome reconstituted cells………………………………………………………41 Figure 6. PPARγ attenuated NLRP3 inflammasome complex formation in HEK293T cells………………………………………………………….42 Figure 7. PPARγ was co-localized with NLRP3 in peritoneal macrophages and NLRP3 inflammasome reconstituted HEK293T cells………………43 Figure 8. PPARγ was interacted with NLRP3…………………………...45 Figure 9. Degradation of PPARγ during inflammasome activation……46 Figure 10. NF-κB and proteasome pathways mediated PPARγ degradation during inflammasome activation………………………………………47 Figure 11. Postulated mechanism of PPARγ in inflammasome activation …………………………………………………………………………...48

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