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研究生:李宗玄
研究生(外文):Tzong-Shyuan Lee
論文名稱:第一型血基質氧化脢之抗發炎作用
論文名稱(外文):The anti-inflammatory effect of heme oxygenase-1
指導教授:趙麗洋
指導教授(外文):Lee-Young Chau
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:2002
畢業學年度:90
語文別:英文
論文頁數:90
中文關鍵詞:血基質氧化脢介白質-1015-去氧前列腺素J2p38分裂原活化蛋白質激脢腫瘤壞死因子一氧化氮核因子-kB
外文關鍵詞:heme oxygenaseHOinterleukin-10IL-1015-deoxy-△1214 -prostaglandin J2p38 mitogen-activated protein kinasetumor necrosis factor-aNOnuclear factor-kBNF-kB
相關次數:
  • 被引用被引用:0
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摘要
血基質氧化脢(heme oxygenase, HO)在血基質代謝作用中過程中扮演重要的角色,它將血基質分解為膽綠素(biliverdin)、一氧化碳(CO)以及游離鐵(free iron);目前已知有三種型式的血基質氧化脢存在於生物體內,其中第二型 (HO-2)與第三型(HO-3)是持續表現型(constitutive form),而第一型(HO-1)是誘發型(inducible form)。在此篇報告中我們發現兩種抗發炎物質: 介白質-10 (interleukin-10, IL-10) 和15-去氧前列腺素J2 (15-deoxy-△12,14 -prostaglandin J2 , 15d-PGJ2)可以有效地誘發老鼠巨噬細胞表現HO-1,而這個過程是透過p38分裂原活化蛋白質激脢(p38 mitogen-activated protein kinase)所調控。 將與HO-1訊息核醣核酸(mRNA)序列互補之寡去氧核醣核酸(oligodeoxynucleotide)片段轉染(transfect)至細胞內可以有效抑制IL-10和15d-PGJ2防止內毒素 (lipopolysaccharide, LPS)所誘發產生的腫瘤壞死因子(tumor necrosis factor-a) 及一氧化氮(NO)之生成;另外,利用HO抑制劑:鋅初紫質(zinc protoporphyrin, ZnPP) 或CO清除者:血紅素(hemoglobin) ,也可以有效抑制IL-10和15d-PGJ2的抗發炎作用。除此之外, 15d-PGJ2 所誘發之HO-1可以藉由抑制LPS所引發的核因子-kB (nuclear factor-kB, NF-kB)活化作用來達到抗發炎的作用。將IL-10注射到小老鼠腹腔中可以誘發HO-1表現,同時可以保護小老鼠免於LPS所引發之敗血症而死亡,而這個保護作用可因ZnPP的處理而減弱;另外的實驗也証明CO的確在IL-10的保護作用中扮演重要角色。總而言之,這些發現支持HO-1/CO的確在IL-10和15d-PGJ2 的抗發炎作用中扮演關鍵性的角色,而這些發現在未來也許可以提供治療炎症疾病的新策略。

Abstract
Heme oxygenase (HO) is the key enzyme responsible for the physiological breakdown of heme into equimolar amounts of biliverdin, carbon monoxide (CO), and iron. Three isoforms (HO-1, HO-2, and HO-3) have been identified, and HO-1is recognized as a major heat shock/stress response protein. Here, we demonstrate that two anti-inflammatory agents, interleukin-10 (IL-10) and 15-deoxy-Δ12,14- prostaglandin J2 (15d-PGJ2) are potent inducers of HO-1 in murine macrophages. The induction of HO-1 by these two agents appeares to be mediated via a p38 mitogen-activated protein kinase dependent pathway. Transfection with antisense oligodeoxynucleotides (ODN) complementary to HO-1 mRNA significantly suppressed the anti-inflammatory effects of IL-10 and 15d-PGJ2 on lipopoly- saccharide (LPS)-induced tumor necrosis factor-a (TNF-a) and nitric oxide (NO) production in macrophages. Cotreatment with HO competitive inhibitor, zinc protoporphyrin (ZnPP) or CO scavenger, hemoglobin (Hb), also significantly blocked their anti-inflammatory effects. Furthermore, the anti-inflammatory effect of HO-1 induced by 15d-PGJ2 acts by inhibiting the degradation of the NF-kB inhibitor IkB, and subsequent translocation to nucleus in LPS-activated cells. The induction of HO-1 was observed in mice receiving IL-10, and the protective effect of IL-10 on LPS-induced lethal endotoxemia was significantly attenuated by cotreatment with ZnPP. Additional experiments revealed the involvement of CO in the anti-inflammatory effect of IL-10 in vivo. Together, these findings support the essential role of HO-1/CO in mediating the anti-inflammatory effects of IL-10 and 15d-PGJ2, and provide a new therapeutic strategy for inflammatory diseases.

English Abstract-------------------------------------------------------------------------------- III
Chinese Abstract------------------------------------------------------------------------------- IV
Introduction
I. Interleukin-10----------------------------------------------------------------------------------1
Immunosuppressive properties of IL-10 in vitro and in vivo----------------------------1
IL-10 receptor complex-----------------------------------------------------------------------3
The signal transduction pathway of IL-10 in mononuclear phagocytes----------------3
Viral IL-10 of Epetein-Barr Virus-----------------------------------------------------------5
II. Biosynthesis of prostaglandins--------------------------------------------------------------5
Mechanisms of prostaglandim action------------------------------------------------------6
15-deoxy-Δ12,14-PGJ2 (15d-PGJ2)-----------------------------------------------------------7
15d-PGJ2 inhibis multiple steps in the NF-kB signaling pathway----------------------8
III. Heme oxygenase-----------------------------------------------------------------------------9
Induction of HO-1 expression-------------------------------------------------------------10
Mechanisms of cytoprotection by HO-1-------------------------------------------------11
IV. Research objective-------------------------------------------------------------------------14
Materials and Methods
Materials-----------------------------------------------------------------------------------------16
Cell culture--------------------------------------------------------------------------------------16
Transfection-------------------------------------------------------------------------------------17
Determination of TNF-a concentration-----------------------------------------------------17
Determination of nitrite production----------------------------------------------------------18
Preparation of nuclear extracts----------------------------------------------------------------18
Western blot analysis---------------------------------------------------------------------------19
Northern blot analysis--------------------------------------------------------------------------20
SDS-PAGE Zymography----------------------------------------------------------------------20
Animal experiments----------------------------------------------------------------------------21
Statistical analysis------------------------------------------------------------------------------22
Results
Induction of HO-1 by IL-10 in murine macrophages--------------------------------------23
P38 MAPK activation in IL-10-induced HO-1 gene expression-------------------------24
IL-10-induced HO-1 inhibits the production of TNF-a in LPS-activated cells--------25
HO-1 mediates the suppressive effect of IL-10 on the production of nitric oxide-----26
HO-1 mediates the suppressive effect of IL-10 on MMP-9-------------------------------26
Induction of HO-1 by IL-10 in vivo----------------------------------------------------------27
15d-PGJ2-induced HO-1 inhibits the production of LPS-induced TNF-a and NO----28
NF-kB-dependent pathway is involved in the inhibitory effect of 15d-PGJ2-----------29
Involvement of p38 MAPK in the induction of HO-1 induced by 15d-PGJ2-----------30
Figures-------------------------------------------------------------------------------------------31
Discussion---------------------------------------------------------------------------------------62
References--------------------------------------------------------------------------------------70

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