臺灣博碩士論文加值系統

巨噬細胞與樹突細胞(Dendritic cells)能辨識病原菌並引發免疫發炎反應，於先天免疫系統扮演重要的角色。Phosphodiesterases 4 (PDE4)為水解cAMP的專一酵素，抑制PDE4以增加兩種細胞內cAMP濃度可減緩多種發炎反應，其中部分反應已被證實主要是由PDE4四個亞型(PDE4A-4D)中的PDE4B參與調控。在本研究中，我們利用PDE4抑制劑與PDE4基因剔除鼠及其細胞進行實驗，發現PDE4B在這些細胞中可以調控更多不同的免疫發炎反應。
已知內毒素lipopolysaccharide (LPS)活化TLR4可誘導巨噬細胞產生促發炎及抗發炎細胞激素。PDE4抑制劑，例如rolipram，被認為是多種發炎反應的免疫抑制劑。在本論文的第一部分中，我們利用LPS刺激小鼠腹腔巨噬細胞，首先發現PDE4抑制劑rolipram會明顯提升LPS所誘導抗發炎細胞激素interleukin-1 receptor antagonist (IL-1Ra)的釋放，此作用是由於增加IL-1Ra的轉錄作用而不是影響其mRNA的穩定度。進一步利用PDE4-/-腹腔巨噬細胞進行實驗顯示，由LPS單獨處理所誘導的IL-1Ra釋放不是受PKA調控，然而與rolipram共同處理所增加的IL-1Ra則是經由抑制PDE4B所致，且需要活化PKA而非Epac訊息傳導路徑。此外，LPS與rolipram兩者作用都需要活化CREB以增加IL-1Ra表現。再者，我們發現在LPS刺激的PDE4B-/-巨噬細胞中，其STAT3 (Tyr705)磷酸化會增加，但此STAT3的活化不是造成該細胞增加IL-1Ra的主要原因。在LPS誘導小鼠敗血症的模型中，PDE4B-/-小鼠的血清中有較多IL-1Ra的累積，此與先前報導該小鼠增加存活率的結果一致。這些研究證實PDE4B在巨噬細胞中會負調控抗發炎細胞激素的產生。在本論文的第二部分中，我們發現處理rolipram或剔除PDE4B可顯著降低小鼠骨髓細胞分化為CD11c+未成熟樹突細胞數以及細胞表面CD11c的表現量，但剔除PDE4A與4D則無此抑制作用。此外，於LPS誘導樹突細胞成熟過程中，rolipram或剔除PDE4B會使CD11c+樹突細胞群更為下降。再者，我們使用定量PCR方法檢測小鼠樹突細胞內Toll-like receptor (TLR)的表現，結果顯示，以LPS處理細胞4小時，TLR1、2、3、6、7與9的mRNA表現量呈顯著上升，而24-36小時後其表現量均會回至基礎值。在這些LPS所誘導的TLRs中，TLR1, 6, 7, 與9的表現會被rolipram顯著抑制，而主要是經由抑制PDE4B所致，顯示PDE4B對於這些先天免疫受體的表現有不可或缺的重要性。在TLR7促效劑imiquimod誘導的乾癬模型中，我們發現PDE4抑制劑可有效減緩小鼠乾癬性皮膚炎的嚴重程度。這些結果證實PDE4，主要是PDE4B，在發炎狀況下會參與調控樹突細胞的分化與免疫功能。綜合上述結果，我們認為研發PDE4B選擇性抑制劑應能保留非選擇性PDE4抑制劑的療效，然而去除其負作用。

Macrophages and dendritic cells (DCs) are important in innate immune system, where they recognize pathogens and initiate inflammatory responses. Elevation of cAMP by inhibition of phosphodieasterases 4 (PDE4), enzymes that degrade cAMP with high affinity, in these cells is known to suppress various inflammatory responses. Among the four PDE4 isoforms (PDE4A-4D), PDE4B has been shown to play a major role in some of these responses. In this study, using PDE4 inhibitors and PDE4-deficient mice and cells, we demonstrate that PDE4B is involved in modulating additional immune responses in these cells under endotoxin lipopolysaccharide (LPS) stimulation.
Activation of TLR4 by LPS is known to induce both pro-inflammatory and anti-inflammatory cytokine production in macrophages. Here in the first part of the study, we show that PDE4 inhibitors, such as rolipram, enhance the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1Ra) secretion in LPS-stimulated mouse peritoneal macrophages, and this response was regulated at the transcriptional level rather than an increased IL-1Ra mRNA stability. Studies with PDE4-deficient macrophages revealed that the IL-1Ra upregulation elicited by LPS alone is PKA-independent, whereas the rolipram-enhanced response was mediated by inhibition of only PDE4B, one of the three PDE4 isoforms expressed in macrophages, and it requires PKA but not Epac activity. However, both pathways activate CREB to induce IL-1Ra expression. PDE4B ablation also promoted STAT3 phosphorylation (Tyr705) to LPS stimulation, but this STAT3 activation is not entirely responsible for the IL-1Ra upregulation in PDE4B-deficient macrophages. In a model of LPS-induced sepsis, only PDE4B-deficient mice displayed an increased circulating IL-1Ra, suggesting a protective role of PDE4B inactivation in vivo. These findings demonstrate that PDE4B negatively modulates anti-inflammatory cytokine expression in macrophages. In the second part of the study, we demonstrate that during in vitro differentiation of mouse bone marrow (BM) cells to immature DCs (imDCs), rolipram or ablation of PDE4B, but PDE4A or PDE4D, significantly reduced CD11c+ imDC population and the cell surface level of CD11c. The CD11c+ population was further decreased by rolipram and PDE4B ablation following LPS induction of DC maturation. Quantitative PCR analysis revealed that the mRNA expression of Toll-like receptor (TLR) 1, 2, 3, 6, 7, and 9 in BMDCs was markedly upregulated at 4 h of LPS stimulation and then declined to near or lower than basal levels at 24 or 36 h. Among these TLRs, the induction of TLR1, 6, 7, and 9 mRNA was greatly inhibited by rolipram and this inhibition was shown to be mediated mainly by inhibition of PDE4B, indicating an essential role of PDE4B in the expression of these innate immune receptors. In a murine model of TLR7 agonist-induced psoriasis, we further showed that PDE4 inhibitor significantly attenuated the severity of psoriatic symptoms in mice treated with imiquimod. These data demonstrate an important role of PDE4, particularly PDE4B, in regulation of DC development and functions under inflammatory conditions. Taken together, our findings provide further evidence that the development of PDE4B-selective inhibitor should retain the therapeutic benefits but devoid the side effects of non-selective PDE4 inhibitors.

Declaration………………………………………………….……………...........…………………….i
中文摘要………………………………………………….………………………..........………..ii-iii
Abstract………………………………………………….………..……….....……...………...…iv-v
Acknowledgments…………………………....…………………..….........….…vi-vii
Table of Contents…………………………………………………..............viii-ix
List of Figures……………………………………………………….................x-xi
List of tables……………………………………………………..…………………...……….....xii
Abbreviations……………………………………….………….……………......……..xiii-xiv
Chapter 1: Phosphodiesterase 4B negatively regulates endotoxin-activated
interleukin-1 receptor antagonist responses in macrophages…....……......................................1
1-1 Introduction……………………………………………………...……….…...…………...2-5
1-2 Materials and Methods……………………………….………………...………….……….6
1-2-1 Reagents…………………………………………........…………...………….……..6
1-2-2 Cell line……………………………….........…………………...……………………6
1-2-3 Mice…………………………………………..........………………….....…………6-7
1-2-4 Primary macrophages………........………………......…………7-8
1-2-5 RNA isolation, cDNA synthesis, and
quantitative PCR…….……....................…..……8-9
1-2-6 RNA stability assay……………………........……...………………..9
1-2-7 Western blot analysis……………........………...……..…9-10
1-2-8 LPS-induced systemic inflammation.…...........…10
1-2-9 Cytokine measurement………………………...........………...…10
1-2-10 Cell viability assay…………………........……...…………10-11
1-2-11 Statistical analysis……………………...……………..…11
1-3 Results………………………………………………………………………….........…...…….12
1-3-1 Inhibition of PDE4 upregulates LPS-induced
IL-1Ra production in mouse macrophages….....12-13
1-3-2 PDE4 inhibitor does not alter intracellular
form IL-1Ra mRNA level or cell viability
in LPS-stimulated mouse peritoneal macrophages
......................................….....13-14
1-3-3 Inhibition of PDE4 does not increase IL-1Ra
mRNA stability……..........................………..14
1-3-4 Ablation of PDE4B increases LPS-induced
IL-1Ra production in macrophage……...….……....14-15
1-3-5 Cyclic AMP-PKA signaling mediates the
stimulating effects of PDE4B ablation and
rolipram inhibition on IL-1Ra productio....…15-16
1-3-6 LPS-induced IL-1Ra production in PDE4B null
macrophages requires both PKA-dependent and
PKA-independent CREB activation….........…….16-17
1-3-7 STAT3 activation elicited by PDE4B ablation
is not fully responsible for the observed
IL-1Ra upregulation……………......…………………......…17-19
1-3-8 Serum level of IL-1Ra is elevated in PDE4B-
deficient mice during LPS-induced sepsis....19-20
1-4 Discussion…………………….....…………………………………………………....….21-25
1-5 References…………………….....………………………………………………....…….26-30
Chapter 2: Phosphodiesterase 4B regulates cell differentiation and TLR expression in bone marrow-derived dendritic cells and its potential function…..….......….31
2-1 Introduction…………………………………………………….....………....…………32-39
2-2 Materials and Methods………………………………..…………………...………….…40
2-2-1 Reagents…………………………………............………………………………….40
2-2-2 Mice……………………………………...............……………………………………40
2-2-3 Generation of bone marrow-derived dendritic
cells (BMDCs)….….........................…..40-41
2-2-4 RNA isolation, cDNA synthesis, and
quantitative PCR………….....................………41-42
2-2-5 Fluorescence-activated cell sorting (FACS)
analysis by flow cytometry…....................42
2-2-6 Induction of psoriasis-like skin inflammation
by imiquimod (IMQ)….….......................…..42
2-2-7 Severity scoring of skin inflammation…………...42-43
2-2-8 Statistical analysis……………………..………………………………..…….43
2-3 Results………………………………………………............………….………………………44
2-3-1 Ablation of PDE4B suppresses bone marrow-derived
dendritic cell differentiation………….………......44-45
2-3-2 Inhibition of PDE4 reduces CD11c+ cell
population during LPS- or OVA-induced
dendritic cell maturation……………………......……………45-46
2-3-3 LPS induces PDE4B mRNA expression in bone
marrow-derived DCs…………………………………………………………....46-47
2-3-4 Inhibition of PDE4 downregulates pattern
recognition receptor expression in dendritic
cells during LPS-induced cell maturation……..47-49
2-3-5 Effects of PDE4 ablation on TLR mRNA
expression during LPS-induced DC maturation…49-51
2-3-6 Inhibition of PDE4 attenuates the severity
of imiquimod (IMQ)-induced psoriasis-like
inflammation……………………………................……..…51-52
2-4 Discussion………………………………………........……………………………….….53-57
2-5 References………………………………………........……………………………..……58-65
Figures and Figure Legends………..………………………………………………...66-99
Tables……………..………………..………………………………………...........……….….…100
Appendix…………………………………..……..……........………………………..……101-104

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