臺灣博碩士論文加值系統

免疫系統在敗血症(sepsis)的病理發展過程中扮演了重要角色。單核球為先天性免疫中主要作用的細胞，它可以說是人體的免疫第一道防線。在許多文獻中顯示單核球在人體遭受外來病菌如：細菌、病毒、黴菌等感染時，可以藉由分泌細胞生長激素(cytokine)及表現某些受體趨使單核球到達發炎的位置作用並促使發炎細胞產生蛋白分解酵素(proteinase)加速組織的破壞。當受到革蘭氏陰性菌(Gram-negative)感染時，主要是由外膜的脂多醣體(LPS, Lipopolysaccharide)對宿主的免疫造成刺激，此時單核球藉由細胞膜上的CD14幫助LPS結合到Toll-like receptor，活化先天性免疫，進一步促使單核球的活化，當單核球活化時，基質金屬蛋白酵素(Matrix metalloproteinase, MMPs)由單核球釋放，對組織造成傷害。
本研究利用了西方點墨法(Western blotting)與電泳酵素分析法(SDS-PAGE Gelatin Zymography)觀察人類初級單核球細胞與THP-1細胞之MMP-9表現與活性，發現carprofen與caffeic acid phenethyl ester (CAPE)具有抑制單核球MMP-9蛋白表現與活性的能力。接著使用RT-PCR以及Transfection，結果顯示carprofen與caffeic acid phenethyl ester (CAPE)對於MMP-9 mRNA表現有抑制作用。但只有caffeic acid phenethyl ester (CAPE)可抑制NF-κB基因的活化。
　　接著探討藥物對於訊息傳導路徑的影響。首先使用各種MAPK (如: JNK, p38及ERK)、PI3K及NF-κB抑制劑(分別為SP600125、SB203580、PD98059、LY294002、與Parthenolide) ，結果發現除了SB203580以外，其他的抑制劑都可以抑制MMP-9的活性與蛋白表現，可以推測在LPS刺激THP-1細胞分泌MMP-9的路徑；主要被活化的訊息為JNK、ERK、Akt和NF-κB。最後以西方點墨法發現carprofen對於p38、JNK和ERK的活化具有抑制作用，這個結果可以解釋carprofen對MMP-9的抑制作用可能並非來自抑制的NF-κB活化。而caffeic acid phenethyl ester (CAPE)能夠抑制ERK及Akt的活化，而更詳細的分子機轉還需要進一步的討論。

Human immune system plays an important role in the pathogenesis of sepsis. In human innate immune system, monocytes are the key element and served as a critical role of defense. Inflammatory monocytes secret cytokine and express chemokine receptor in response to microbial and attract immune cell to the inflammatory site. Lipopolysaccharide (LPS) is main componment of cell wall in Gram-negative bacteria.Under the stimulation of LPS, monocytes will help LPS binds to Toll-like receptor (TLR) by CD14 on their cell membrane. And then innate immunity activation, monocytes may release MMPs (Matrix metalloproteinase). Excess release of MMPs may cause damage to the tissue.
We found carprofen and caffeic acid phenethyl ester (CAPE) showed obviously inhibitory effect on MMP-9 production in human monocytes and THP-1 cells. And we also found the effect of carprofen and caffeic acid phenethyl ester (CAPE) on MMP-9 mRNA expression and NF-κB activation under LPS stimulation by RT-PCR and Transfection in THP-1 cells. Under LPS stimulation,the expression of MMP-9 mRNA was increased with time and inhibited by carprofen and caffeic acid phenethyl ester (CAPE). The activation of NF-κB gene under LPS stimulation in THP-1 cells was inhibited by caffeic acid phenethyl ester (CAPE), but not affected by carprofen.
And we use inhibitors of JNK, p38, ERK, PI3K and NF-κB (SP600125, SB203580, PD98059, LY294002 and Parthenolide, respectively) to investigate the effect of carprofen and caffeic acid phenethyl ester(CAPE)on MMP-9 activation and protein expression. We found JNK, ERK, Akt and NF-κB inhibitors inhibited MMP-9 activation and protein expression. JNK、ERK、Akt and NF-κB might be the major signal pathway that regulated the expression of MMP-9. Carprofen and caffeic acid phenethyl ester (CAPE) inhibited activation of JNK, ERK and Akt. We also found that carprofen inhibited phosphorylation of p38, JNK and ERK. The results may explain that the inhibitory effect of MMP-9 by carprofen was not owing to suppress the activation NF-κB. CAPE inhibited phosphorylation of ERK and Akt, but it has no effect on phosphorylation of p38. We predicted the inhibition effects of MMP-9 by CAPE may not only inhibited NF-κB but also AP-1.

目錄
縮寫表……………………………………………………….2
中文摘要…………………………………………………….4
英文摘要…………………………………………………….6
壹、緒論………………………………………………….....8
貳、材料與方法
實驗材料……………………….……………………….29
實驗方法…………………………….………………….35
參、結果…………………………………………………....48
肆、討論…………………………………………………....62
伍、結論與展望……………………………………………70
陸、 附圖…………………………………………………..71
柒、圖表…………………………………………………....74
捌、參考文獻………………………………………………102

Abraham E and Singer M (2007) Mechanisms of sepsis-induced organ dysfunction. Crit Care Med 35(10):2408-2416.
Adib-Conquy M, Adrie C, Fitting C, Gattolliat O, Beyaert R and Cavaillon JM (2006) Up-regulation of MyD88s and SIGIRR, molecules inhibiting Toll-like receptor signaling, in monocytes from septic patients. Crit Care Med 34(9):2377-2385.
Ahmad-Nejad P, Hacker H, Rutz M, Bauer S, Vabulas RM and Wagner H (2002) Bacterial CpG-DNA and lipopolysaccharides activate Toll-like receptors at distinct cellular compartments. Eur J Immunol 32(7):1958-1968.
Akira S and Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4(7):499-511.
Alessi DR, Deak M, Casamayor A, Caudwell FB, Morrice N, Norman DG, Gaffney P, Reese CB, MacDougall CN, Harbison D, Ashworth A and Bownes M (1997a) 3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase. Curr Biol 7(10):776-789.
Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB and Cohen P (1997b) Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 7(4):261-269.
Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J and Pinsky MR (2001) Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 29(7):1303-1310.
Banyai L, Tordai H and Patthty L (1996) Structure and domain-domain interactions of the gelatin binding site of human 72-kilodalton type IV collagenase (gelatinase A, matrix metalloproteinase 2). J Biol Chem 271(20):12003-12008.
Bjorkbacka H, Fitzgerald KA, Huet F, Li X, Gregory JA, Lee MA, Ordija CM, Dowley NE, Golenbock DT and Freeman MW (2004) The induction of macrophage gene expression by LPS predominantly utilizes Myd88-independent signaling cascades. Physiol Genomics 19(3):319-330.
Blackwell TS and Christman JW (1997) The role of nuclear factor-kappa B in cytokine gene regulation. Am J Respir Cell Mol Biol 17(1):3-9.
Bode W (1995) A helping hand for collagenases: the haemopexin-like domain. Structure 3(6):527-530.
Bode W, Gomis-Ruth FX and Stockler W (1993) Astacins, serralysins, snake venom and matrix metalloproteinases exhibit identical zinc-binding environments (HEXXHXXGXXH and Met-turn) and topologies and should be grouped into a common family, the ''metzincins''. FEBS Lett 331(1-2):134-140.
Bosca F, Marin ML and Miranda MA (2001) Photoreactivity of the nonsteroidal anti-inflammatory 2-arylpropionic acids with photosensitizing side effects. Photochem Photobiol 74(5):637-655.
Brinckerhoff CE and Matrisian LM (2002) Matrix metalloproteinases: a tail of a frog that became a prince. Nat Rev Mol Cell Biol 3(3):207-214.
Brunialti MK, Martins PS, Barbosa de Carvalho H, Machado FR, Barbosa LM and Salomao R (2006) TLR2, TLR4, CD14, CD11B, and CD11C expressions on monocytes surface and cytokine production in patients with sepsis, severe sepsis, and septic shock. Shock 25(4):351-357.
Busiek DF, Baragi V, Nehring LC, Parks WC and Welgus HG (1995) Matrilysin expression by human mononuclear phagocytes and its regulation by cytokines and hormones. J Immunol 154(12):6484-6491.
Campbell SE, Nasir L, Argyle DJ and Bennett D (2001) Molecular cloning and characterization of canine metalloproteinase-9 gene promoter. Gene 273(1):81-87.
Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296(5573):1655-1657.
Carpenter CL, Duckworth BC, Auger KR, Cohen B, Schaffhausen BS and Cantley LC (1990) Purification and characterization of phosphoinositide 3-kinase from rat liver. J Biol Chem 265(32):19704-19711.
Carter AB, Monick MM and Hunninghake GW (1999) Both Erk and p38 kinases are necessary for cytokine gene transcription. Am J Respir Cell Mol Biol 20(4):751-758.
Cavaillon JM, Adib-Conquy M, Fitting C, Adrie C and Payen D (2003) Cytokine cascade in sepsis. Scand J Infect Dis 35(9):535-544.
Chiao C, Carothers AM, Grunberger D, Solomon G, Preston GA and Barrett JC (1995) Apoptosis and altered redox state induced by caffeic acid phenethyl ester (CAPE) in transformed rat fibroblast cells. Cancer Res 55(16):3576-3583.
Chirco R, Liu XW, Jung KK and Kim HR (2006) Novel functions of TIMPs in cell signaling. Cancer Metastasis Rev 25(1):99-113.
Christman JW, Lancaster LH and Blackwell TS (1998) Nuclear factor kappa B: a pivotal role in the systemic inflammatory response syndrome and new target for therapy. Intensive Care Med 24(11):1131-1138.
Cobb MH and Goldsmith EJ (1995) How MAP kinases are regulated. J Biol Chem 270(25):14843-14846.
Corbel M, Belleguic C, Boichot E and Lagente V (2002) Involvement of gelatinases (MMP-2 and MMP-9) in the development of airway inflammation and pulmonary fibrosis. Cell Biol Toxicol 18(1):51-61.
Cuschieri J and Maier RV (2005) Mitogen-activated protein kinase (MAPK). Crit Care Med 33(12 Suppl):S417-419.
Davis RJ (1993) The mitogen-activated protein kinase signal transduction pathway. J Biol Chem 268(20):14553-14556.
Davis RJ (1999) Signal transduction by the c-Jun N-terminal kinase. Biochem Soc Symp 64:1-12.
Dhanaraj V, Ye QZ, Johnson LL, Hupe DJ, Ortwine DF, Dunbar JB, Jr., Rubin JR, Pavlovsky A, Humblet C and Blundell TL (1996) X-ray structure of a hydroxamate inhibitor complex of stromelysin catalytic domain and its comparison with members of the zinc metalloproteinase superfamily. Structure 4(4):375-386.
Ferrero E and Goyert SM (1988) Nucleotide sequence of the gene encoding the monocyte differentiation antigen, CD14. Nucleic Acids Res 16(9):4173.
Fingerle G, Pforte A, Passlick B, Blumenstein M, Strobel M and Ziegler-Heitbrock HW (1993) The novel subset of CD14+/CD16+ blood monocytes is expanded in sepsis patients. Blood 82(10):3170-3176.
Fogg DK, Sibon C, Miled C, Jung S, Aucouturier P, Littman DR, Cumano A and Geissmann F (2006) A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311(5757):83-87.
Gentil A, Le Page F and Sarasin A (1997) The consequence of translesional replication of unique UV-induced photoproducts. Biol Chem 378(11):1287-1292.
Giroir BP, Johnson JH, Brown T, Allen GL and Beutler B (1992) The tissue distribution of tumor necrosis factor biosynthesis during endotoxemia. J Clin Invest 90(3):693-698.
Gomez DE, Alonso DF, Yoshiji H and Thorgeirsson UP (1997) Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol 74(2):111-122.
Goodwin JS (1984) Mechanism of action of nonsteroidal anti-inflammatory agents. Am J Med 77(1A):57-64.
Guha M and Mackman N (2001) LPS induction of gene expression in human monocytes. Cell Signal 13(2):85-94.
Gupta S, Barrett T, Whitmarsh AJ, Cavanagh J, Sluss HK, Derijard B and Davis RJ (1996) Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J 15(11):2760-2770.
Haeffner-Cavaillon N, Cavaillon JM, Etievant M, Lebbar S and Szabo L (1985) Specific binding of endotoxin to human monocytes and mouse macrophages: serum requirement. Cell Immunol 91(1):119-131.
Haeffner-Cavaillon N, Chaby R, Cavaillon JM and Szabo L (1982) Lipopolysaccharide receptor on rabbit peritoneal macrophages. I. Binding characteristics. J Immunol 128(5):1950-1954.
Hale KK, Trollinger D, Rihanek M and Manthey CL (1999) Differential expression and activation of p38 mitogen-activated protein kinase alpha, beta, gamma, and delta in inflammatory cell lineages. J Immunol 162(7):4246-4252.
Han YP, Tuan TL, Hughes M, Wu H and Garner WL (2001) Transforming growth factor-beta - and tumor necrosis factor-alpha -mediated induction and proteolytic activation of MMP-9 in human skin. J Biol Chem 276(25):22341-22350.
Hashimoto K, Nagao Y, Kato K, Mori Y and Ito A (1998) Human urinary trypsin inhibitor inhibits the activation of pro-matrix metalloproteinases and proteoglycans release in rabbit articular cartilage. Life Sci 63(3):205-213.
Hastbacka J, Hynninen M, Kolho E, Pettila V, Tervahartiala T, Sorsa T and Lauhio A (2007) Collagenase 2/matrix metalloproteinase 8 in critically ill patients with secondary peritonitis. Shock 27(2):145-150.
Haveman JW, Muller Kobold AC, Tervaert JW, van den Berg AP, Tulleken JE, Kallenberg CG and The TH (1999) The central role of monocytes in the pathogenesis of sepsis: consequences for immunomonitoring and treatment. Neth J Med 55(3):132-141.
Haziot A, Chen S, Ferrero E, Low MG, Silber R and Goyert SM (1988) The monocyte differentiation antigen, CD14, is anchored to the cell membrane by a phosphatidylinositol linkage. J Immunol 141(2):547-552.
He C (1996) Molecular mechanism of transcriptional activation of human gelatinase B by proximal promoter. Cancer Lett 106(2):185-191.
Heil F, Ahmad-Nejad P, Hemmi H, Hochrein H, Ampenberger F, Gellert T, Dietrich H, Lipford G, Takeda K, Akira S, Wagner H and Bauer S (2003) The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. Eur J Immunol 33(11):2987-2997.
Hoffmann U, Bertsch T, Dvortsak E, Liebetrau C, Lang S, Liebe V, Huhle G, Borggrefe M and Brueckmann M (2006) Matrix-metalloproteinases and their inhibitors are elevated in severe sepsis: prognostic value of TIMP-1 in severe sepsis. Scand J Infect Dis 38(10):867-872.
Hooper NM (1994) Families of zinc metalloproteases. FEBS Lett 354(1):1-6.
Huang MT, Ma W, Yen P, Xie JG, Han J, Frenkel K, Grunberger D and Conney AH (1996) Inhibitory effects of caffeic acid phenethyl ester (CAPE) on 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion in mouse skin and the synthesis of DNA, RNA and protein in HeLa cells. Carcinogenesis 17(4):761-765.
Huhtala P, Tuuttila A, Chow LT, Lohi J, Keski-Oja J and Tryggvason K (1991) Complete structure of the human gene for 92-kDa type IV collagenase. Divergent regulation of expression for the 92- and 72-kilodalton enzyme genes in HT-1080 cells. J Biol Chem 266(25):16485-16490.
Ip YT and Davis RJ (1998) Signal transduction by the c-Jun N-terminal kinase (JNK)--from inflammation to development. Curr Opin Cell Biol 10(2):205-219.
Janknecht R and Hunter T (1997) Activation of the Sap-1a transcription factor by the c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase. J Biol Chem 272(7):4219-4224.
Jin UH, Song KH, Motomura M, Suzuki I, Gu YH, Kang YJ, Moon TC and Kim CH (2008) Caffeic acid phenethyl ester induces mitochondria-mediated apoptosis in human myeloid leukemia U937 cells. Mol Cell Biochem 310(1-2):43-48.
Kapeller R and Cantley LC (1994) Phosphatidylinositol 3-kinase. Bioessays 16(8):565-576.
Kunkel SL, Chensue SW and Phan SH (1986) Prostaglandins as endogenous mediators of interleukin 1 production. J Immunol 136(1):186-192.
Kyriakis JM and Avruch J (1996) Sounding the alarm: protein kinase cascades activated by stress and inflammation. J Biol Chem 271(40):24313-24316.
Lafleur MA, Handsley MM and Edwards DR (2003) Metalloproteinases and their inhibitors in angiogenesis. Expert Rev Mol Med 5(23):1-39.
Landoni MF, Foot R, Frean S and Lees P (1996) Effects of flunixin, tolfenamic acid, R(-) and S(+) ketoprofen on the response of equine synoviocytes to lipopolysaccharide stimulation. Equine Vet J 28(6):468-475.
Langton KP, Barker MD and McKie N (1998) Localization of the functional domains of human tissue inhibitor of metalloproteinases-3 and the effects of a Sorsby''s fundus dystrophy mutation. J Biol Chem 273(27):16778-16781.
Lu HT, Yang DD, Wysk M, Gatti E, Mellman I, Davis RJ and Flavell RA (1999) Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. EMBO J 18(7):1845-1857.
Masure S, Proost P, Van Damme J and Opdenakker G (1991) Purification and identification of 91-kDa neutrophil gelatinase. Release by the activating peptide interleukin-8. Eur J Biochem 198(2):391-398.
Mathison JC, Tobias PS, Wolfson E and Ulevitch RJ (1992) Plasma lipopolysaccharide (LPS)-binding protein. A key component in macrophage recognition of gram-negative LPS. J Immunol 149(1):200-206.
Medvedev AE, Lentschat A, Wahl LM, Golenbock DT and Vogel SN (2002) Dysregulation of LPS-induced Toll-like receptor 4-MyD88 complex formation and IL-1 receptor-associated kinase 1 activation in endotoxin-tolerant cells. J Immunol 169(9):5209-5216.
Michaluart P, Masferrer JL, Carothers AM, Subbaramaiah K, Zweifel BS, Koboldt C, Mestre JR, Grunberger D, Sacks PG, Tanabe T and Dannenberg AJ (1999) Inhibitory effects of caffeic acid phenethyl ester on the activity and expression of cyclooxygenase-2 in human oral epithelial cells and in a rat model of inflammation. Cancer Res 59(10):2347-2352.
Min D, Moore AG, Bain MA, Breit SN and Lyons JG (2002) Activation of macrophage promatrix metalloproteinase-9 by lipopolysaccharide-associated proteinases. J Immunol 168(5):2449-2455.
Minden A and Karin M (1997) Regulation and function of the JNK subgroup of MAP kinases. Biochim Biophys Acta 1333(2):F85-104.
Mirzoeva OK, Sud''ina GF, Pushkareva MA, Korshunova GA, Sumbatian NV and Varfolomeev SD (1995) [Lipophilic derivatives of caffeic acid as lipoxygenase inhibitors with antioxidant properties]. Bioorg Khim 21(2):143-151.
Murphy G and Willenbrock F (1995) Tissue inhibitors of matrix metalloendopeptidases. Methods Enzymol 248:496-510.
Nagaoka T, Banskota AH, Tezuka Y, Midorikawa K, Matsushige K and Kadota S (2003) Caffeic acid phenethyl ester (CAPE) analogues: potent nitric oxide inhibitors from the Netherlands propolis. Biol Pharm Bull 26(4):487-491.
Nagase H and Woessner JF, Jr. (1999) Matrix metalloproteinases. J Biol Chem 274(31):21491-21494.
Nakamura T, Ebihara I, Shimada N, Shoji H and Koide H (1998) Modulation of plasma metalloproteinase-9 concentrations and peripheral blood monocyte mRNA levels in patients with septic shock: effect of fiber-immobilized polymyxin B treatment. Am J Med Sci 316(6):355-360.
Natarajan K, Singh S, Burke TR, Jr., Grunberger D and Aggarwal BB (1996) Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B. Proc Natl Acad Sci U S A 93(17):9090-9095.
Nathan CF (1987) Secretory products of macrophages. J Clin Invest 79(2):319-326.
Nelson JE and Harris RE (2000) Inverse association of prostate cancer and non-steroidal anti-inflammatory drugs (NSAIDs): results of a case-control study. Oncol Rep 7(1):169-170.
Neri LM, Borgatti P, Capitani S and Martelli AM (2002) The nuclear phosphoinositide 3-kinase/AKT pathway: a new second messenger system. Biochim Biophys Acta 1584(2-3):73-80.
Nishida E and Gotoh Y (1993) The MAP kinase cascade is essential for diverse signal transduction pathways. Trends Biochem Sci 18(4):128-131.
Norrish AE, Jackson RT and McRae CU (1998) Non-steroidal anti-inflammatory drugs and prostate cancer progression. Int J Cancer 77(4):511-515.
Opdenakker G, Masure S, Grillet B and Van Damme J (1991) Cytokine-mediated regulation of human leukocyte gelatinases and role in arthritis. Lymphokine Cytokine Res 10(4):317-324.
Orban Z, Mitsiades N, Burke TR, Jr., Tsokos M and Chrousos GP (2000) Caffeic acid phenethyl ester induces leukocyte apoptosis, modulates nuclear factor-kappa B and suppresses acute inflammation. Neuroimmunomodulation 7(2):99-105.
Owen CA and Campbell EJ (1999) The cell biology of leukocyte-mediated proteolysis. J Leukoc Biol 65(2):137-150.
Paemen L, Jansen PM, Proost P, Van Damme J, Opdenakker G, Hack E and Taylor FB (1997) Induction of gelatinase B and MCP-2 in baboons during sublethal and lethal bacteraemia. Cytokine 9(6):412-415.
Parks WC, Wilson CL and Lopez-Boado YS (2004) Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol 4(8):617-629.
Pentland AP, Shapiro SD and Welgus HG (1995) Agonist-induced expression of tissue inhibitor of metalloproteinases and metalloproteinases by human macrophages is regulated by endogenous prostaglandin E2 synthesis. J Invest Dermatol 104(1):52-57.
Pugin J, Widmer MC, Kossodo S, Liang CM, Preas HLn and Suffredini AF (1999) Human neutrophils secrete gelatinase B in vitro and in vivo in response to endotoxin and proinflammatory mediators. Am J Respir Cell Mol Biol 20(3):458-464.
Rahmsdorf HJ (1996) Jun: transcription factor and oncoprotein. J Mol Med 74(12):725-747.
Rao CV, Desai D, Simi B, Kulkarni N, Amin S and Reddy BS (1993) Inhibitory effect of caffeic acid esters on azoxymethane-induced biochemical changes and aberrant crypt foci formation in rat colon. Cancer Res 53(18):4182-4188.
Roberts RO, Jacobson DJ, Girman CJ, Rhodes T, Lieber MM and Jacobsen SJ (2002) A population-based study of daily nonsteroidal anti-inflammatory drug use and prostate cancer. Mayo Clin Proc 77(3):219-225.
Rothe G, Gabriel H, Kovacs E, Klucken J, Stohr J, Kindermann W and Schmitz G (1996) Peripheral blood mononuclear phagocyte subpopulations as cellular markers in hypercholesterolemia. Arterioscler Thromb Vasc Biol 16(12):1437-1447.
Salomao R, Brunialti MK, Kallas EG, Martins PS, Rigato O and Freudenberg M (2002) Lipopolysaccharide-cell interaction and induced cellular activation in whole blood of septic patients. J Endotoxin Res 8(5):371-379.
Sato H and Seiki M (1993) Regulatory mechanism of 92 kDa type IV collagenase gene expression which is associated with invasiveness of tumor cells. Oncogene 8(2):395-405.
Schumann RR, Leong SR, Flaggs GW, Gray PW, Wright SD, Mathison JC, Tobias PS and Ulevitch RJ (1990) Structure and function of lipopolysaccharide binding protein. Science 249(4975):1429-1431.
Serbina NV, Jia T, Hohl TM and Pamer EG (2008) Monocyte-mediated defense against microbial pathogens. Annu Rev Immunol 26:421-452.
Shankavaram UT, DeWitt DL, Funk SE, Sage EH and Wahl LM (1997) Regulation of human monocyte matrix metalloproteinases by SPARC. J Cell Physiol 173(3):327-334.
Shapiro SD, Kobayashi DK, Pentland AP and Welgus HG (1993) Induction of macrophage metalloproteinases by extracellular matrix. Evidence for enzyme- and substrate-specific responses involving prostaglandin-dependent mechanisms. J Biol Chem 268(11):8170-8175.
Shipley JM, Doyle GA, Fliszar CJ, Ye QZ, Johnson LL, Shapiro SD, Welgus HG and Senior RM (1996) The structural basis for the elastolytic activity of the 92-kDa and 72-kDa gelatinases. Role of the fibronectin type II-like repeats. J Biol Chem 271(8):4335-4341.
Simmons DL, Tan S, Tenen DG, Nicholson-Weller A and Seed B (1989) Monocyte antigen CD14 is a phospholipid anchored membrane protein. Blood 73(1):284-289.
Stamenkovic I (2003) Extracellular matrix remodelling: the role of matrix metalloproteinases. J Pathol 200(4):448-464.
Sternlicht MD and Werb Z (2001) How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 17:463-516.
Stocker W, Grams F, Baumann U, Reinemer P, Gomis-Ruth FX, McKay DB and Bode W (1995) The metzincins--topological and sequential relations between the astacins, adamalysins, serralysins, and matrixins (collagenases) define a superfamily of zinc-peptidases. Protein Sci 4(5):823-840.
Su B and Karin M (1996) Mitogen-activated protein kinase cascades and regulation of gene expression. Curr Opin Immunol 8(3):402-411.
Sud''ina GF, Mirzoeva OK, Pushkareva MA, Korshunova GA, Sumbatyan NV and Varfolomeev SD (1993) Caffeic acid phenethyl ester as a lipoxygenase inhibitor with antioxidant properties. FEBS Lett 329(1-2):21-24.
Suzuki T, Hashimoto S, Toyoda N, Nagai S, Yamazaki N, Dong HY, Sakai J, Yamashita T, Nukiwa T and Matsushima K (2000) Comprehensive gene expression profile of LPS-stimulated human monocytes by SAGE. Blood 96(7):2584-2591.
Swantek JL, Cobb MH and Geppert TD (1997) Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) is required for lipopolysaccharide stimulation of tumor necrosis factor alpha (TNF-alpha) translation: glucocorticoids inhibit TNF-alpha translation by blocking JNK/SAPK. Mol Cell Biol 17(11):6274-6282.
Takeda K and Akira S (2004) Microbial recognition by Toll-like receptors. J Dermatol Sci 34(2):73-82.
Thieblemont N, Weiss L, Sadeghi HM, Estcourt C and Haeffner-Cavaillon N (1995) CD14lowCD16high: a cytokine-producing monocyte subset which expands during human immunodeficiency virus infection. Eur J Immunol 25(12):3418-3424.
Tobias PS, Soldau K and Ulevitch RJ (1989) Identification of a lipid A binding site in the acute phase reactant lipopolysaccharide binding protein. J Biol Chem 264(18):10867-10871.
Tuyt LM, Dokter WH, Birkenkamp K, Koopmans SB, Lummen C, Kruijer W and Vellenga E (1999) Extracellular-regulated kinase 1/2, Jun N-terminal kinase, and c-Jun are involved in NF-kappa B-dependent IL-6 expression in human monocytes. J Immunol 162(8):4893-4902.
Ulevitch RJ, Wolfson N, Virca GD, Kim S, Kline L and Mathison JC (1989) Macrophages regulate the host response to bacterial lipopolysaccharides. Prog Clin Biol Res 299:193-202.
Van Wart HE and Birkedal-Hansen H (1990) The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc Natl Acad Sci U S A 87(14):5578-5582.
Vivanco I and Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2(7):489-501.
Wahl LM and Lampel LL (1987) Regulation of human peripheral blood monocyte collagenase by prostaglandins and anti-inflammatory drugs. Cell Immunol 105(2):411-422.
Whitmarsh AJ, Cavanagh J, Tournier C, Yasuda J and Davis RJ (1998) A mammalian scaffold complex that selectively mediates MAP kinase activation. Science 281(5383):1671-1674.
Wilkinson MG and Millar JB (1998) SAPKs and transcription factors do the nucleocytoplasmic tango. Genes Dev 12(10):1391-1397.
Wojtowicz-Praga SM, Dickson RB and Hawkins MJ (1997) Matrix metalloproteinase inhibitors. Invest New Drugs 15(1):61-75.
Wright SD, Ramos RA, Tobias PS, Ulevitch RJ and Mathison JC (1990) CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 249(4975):1431-1433.
Yuasa T, Ohno S, Kehrl JH and Kyriakis JM (1998) Tumor necrosis factor signaling to stress-activated protein kinase (SAPK)/Jun NH2-terminal kinase (JNK) and p38. Germinal center kinase couples TRAF2 to mitogen-activated protein kinase/ERK kinase kinase 1 and SAPK while receptor interacting protein associates with a mitogen-activated protein kinase kinase kinase upstream of MKK6 and p38. J Biol Chem 273(35):22681-22692.
Ziegler-Heitbrock HW (2000) Definition of human blood monocytes. J Leukoc Biol 67(5):603-606.
Ziegler-Heitbrock HW, Fingerle G, Strobel M, Schraut W, Stelter F, Schutt C, Passlick B and Pforte A (1993) The novel subset of CD14+/CD16+ blood monocytes exhibits features of tissue macrophages. Eur J Immunol 23(9):2053-2058.