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研究生:伍婉琳
研究生(外文):Wan-Lin Wu
論文名稱:探討登革病毒感染樹突狀細胞誘導產生環氧酵素二型之分子機轉及其扮演的生物功能
論文名稱(外文):Investigate the molecular mechanisms and biological functions of DV-induced COX-2 expression
指導教授:賴振宏賴振宏引用關係
指導教授(外文):Jenn-Haung Lai
學位類別:博士
校院名稱:國防醫學院
系所名稱:生命科學研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2009
畢業學年度:98
語文別:英文
論文頁數:80
中文關鍵詞:登革病毒樹突狀細胞環氧酵素二型
外文關鍵詞:dengue virusdendritic cellcyclooxygenase-2
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中文摘要
登革熱或登革出血熱是由登革病毒感染所導致的疾病,盛行於熱帶及亞熱帶地區,台灣同屬疫區。目前尚未研發出有效且臨床上可使用的疫苗,瞭解登革病毒的致病機轉以達到治療與預防的目的,顯得更為重要。人類樹突狀細胞為登革病毒感染人體的主要宿主細胞 (primary target cell),我們致力於探討登革病毒感染人類樹突狀細胞所引起的反應,及其與登革病毒的致病機轉之間的相關性。
我們的研究指出,登革病毒感染人類樹突狀細胞後,誘導環氧酵素二型 (COX-2) 及其下游脂質代謝物前列腺素E2 (PGE2) 表現,此現象需透過活化IKK-NFB及MAPK-AP-1的訊息傳導而達成。我們也發現登革病毒感染細胞造成鈣離子的游動,導致細胞內氧化自由基的量提高,進而活化IKK-NFB、MAPK-AP-1及COX-2。登革病毒感染所誘導活化的COX-2雖然不影響登革病毒在人類樹突狀細胞的複製但影響樹突狀細胞受趨化激素19或趨化激素21 (CCL19/CCL21) 誘導的移行作用。抑制登革病毒所誘導產生COX-2或其上游MAPK的活性即抑制樹突狀細胞受趨化激素所誘導的移行作用。進而我們發現登革病毒所活化的COX-2- PGE2能透過autocrine方式作用於PGE2的受體,EP-2及EP-4,傳遞訊息使樹突狀細胞產生高量的趨化激素受體7 (CCR7) 而促使樹突狀細胞趨向CCL19或CCL21移動。
總結我們的研究,發現樹突狀細胞中數個與發炎反應相關的分子會受登革病毒感染而活化,這樣的活化狀態使樹突狀細胞能受趨化激素吸引而移動。我們認為,登革病毒感染所激活的COX-2- PGE2不僅參與登革病毒所誘發的發炎反應,也提供登革病毒在體內散播子代的管道。這樣的發現也提供了研發臨床上治療登革病毒感染造成症狀的藥物的研究方向。
Abstract
A term “bone-breaking fever” is used to describe symptoms of dengue virus (DV)-infected patients in Chinese medicine. We examined the involvement of COX-prostaglandin pathway and its significance in human DC infected by DV. We show that DV infection induced the expression of COX-2 and the production of PGE2. DV infection stimulated NF-B and kinase activities of both IκBα kinase alpha (IKKα) and IKKβ. DV infection also activated MAPKs and AP-1 signalings. Both IKKs-NF-B and MAPKs-AP-1 were upstream of COX-2 activation. Inhibitor studies demonstrate the involvement of several crucial events and molecules, including calcium mobilization, oxidative stress, tyrosine kinase, PI3K, PKC and protein kinase A (PKA) along the activation pathway of COX-2 in DV infection of DC. Different from observations in other target cells, DV-induced activation of COX-2-PGE2 pathway did not affect viral production in DC; however, it enhanced DC migration through induction of CCR7 expression which could be down-regulated by COX-2 inhibitors. Blocking COX-2 or MAPKs activity suppressed DV-induced DC migration. Collectively, the present study reveals not only potential targets to manipulate therapeutically but also potentially unanticipated benefits of COX-2 inhibition beyond anti-inflammation in the treatment of DV infection.
CONTENTS
Page
CHINESE ABSTRACT 1

ABSTRACT 2

INTRODUCTION 3

Dengue virus and DV-induced disease 3

Cell tropism of DV infection 5

Dendritic cell AND Dengue Virus 5

COX-2-PGE2 and inflammation 7

COX-2-PGE2 and CCR7 9

Virus and COX-2-PGE2 10

Objective of this study 11

MATERIAL AND METHOD 12

Culture medium and reagents 12

Establishment of DC 12

Preparation of DV and determination of virus titers 13

Infection of DC with DV 13

RT-PCR 14

Immunocytochemistry staining 14

Flow cytometric analysis 15

Nuclear extract preparation 16

Electrophoresis mobility shift assay (EMSA) 16

Western blotting 17

Immunoprecipitation kinase assay 17

Chemotaxis assay 18

RESULT 20

COX-2 expression was enhanced by DV infection in DC 20

COX-2-PGE2 production was DV replication dependent 20

DV activated NF-B, upstream of COX-2 20

Activation of MAPK-AP-1, upstream of COX-2, signaling
pathway in DV-infected DC 22

Tyrosine kinase, PI-3 kinase, protein kinase A and protein
kinase C were upstream regulators of NF-B, AP-1 and
COX-2 in DV-infected DC 24

Infection of DC by DV-induced generation of ROS 25

The activation of COX-2 and accumulation of ROS in DV-infected
DC was calcium-dependent 26

Infection of DC by other DV2 strains, PL046 and 16681,
induced COX-2 expression and activation of both AP-1
and NF-B DNA-binding activity 26


Blocking ROS-COX-2-PGE2 pathway did not affect
viral production in DC. 27

DV infection induced DC migration which was suppressed by
COX-2 inhibitor. 28

DV-induced DC migration was suppressed by MAPK inhibitors 29

DV-induced CC chemokine receptor 7 expression that was
susceptible to COX-2 inhibition 29

PGE2 through receptors EP2 and EP4 enhanced CCR7
expression in both DV-infected and bystander DC 30

DISSCUSSION 32

The DV-infected DC model provides information that is more
closely to physiological condition 32

Significance of studying the molecular mechanism of DV
induced COX-2 expression. 33

Regulation of DV replication in DC is COX-2-PGE2
independent 35

Triggering DC migration by DV-induced COX-2- PGE2
may contribute to DV-induced immunopathogenesis. 36

REFERENCE 39
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