摘要
Resistin称抗素(也称FIZZ3),是一种含有114个氨基酸的细胞因子。近来发现resistin具有一系列前炎症因子的特征,在炎症中能够诱导血管内皮细胞粘附分子的表达,从而导致白细胞向各个炎症组织中的浸润。尽管resistin在炎症发生中已有不少报道,但其与经典炎症信号途径的关系,在炎症中的作用及其调控机制尚未阐明。
环氧合酶2(COX-2)是前列腺素合成中的一个限速酶。在人体中存在两种不同的COX异构体,分别称为COX-1和COX-2。其中COX-2是一种经过诱导而产生的酶,在正常生理条件下维持较低的表达水平,但在炎症部位表达上调,催化炎性PGs的合成并诱发炎症反应。此外,COX-2的启动子上存在NF-κB的结合元件,可受转录因子NF-κB调控。一些重要的炎症因子例如TNFa和IL-1可通过激活NF-κB而上调COX-2的表达。
本研究以resistin为研究对象,采用real-time PCR、Western Blotting和细胞转染等技术,系统研究了resistin通过经典的炎症信号途径上调COX-2的基因表达及抗炎肽C15对resistin等引起的炎症反应的抑制作用分子机制,结果如下:
1.在巨噬细胞内分别转染猪和小鼠resistin的超表达载体,采用real-timePCR和Western Blotting方法检测细胞内源的COX-2的mRNA和蛋白质水平的表达变化。结果表明,resistin在RAW264.7巨噬细胞系中可以显著地上调COX-2的mRNA和蛋白质的表达。更重要的是,通过原核表达制备了抗resistin的抗体,用抗体处理可以抵消resistin的这种作用。
2.以巨噬细胞为模型,通过负显性IκBα突变体和PDTC这两种抑制物质研究了resistin对COX-2的信号转导途径的调控。结果表明,无论是超表达负显性IκBα突变体载体,还是用抑制剂PDTC刺激,都可以抑制resistin对COX-2的诱导作用。进一步的研究证实,resistin的超表达可以上调NF-κB分子中的p65亚基的表达,进而诱导COX-2的表达水平的上升。
3.以resistin对小鼠巨噬细胞作不同时间梯度的处理,用Western Blotting方法分析resistin对一种MAPKKK激酶TAK1 (Transforming growth factorβactivated kinase 1)的磷酸化程度的影响。结果表明,resistin可以显著上调TAK1的磷酸化水平。
4.以促炎物质resistin,LPS,PA分别和C15共同处理小鼠巨噬细胞,检测炎症基因COX-2和iNOS (inducible nitric oxide synthase)的表达变化。结果表明,炎症基因COX-2和iNOS可以被三种促炎物质诱导表达,并且这种诱导的情况可以显著被C15所抑制住。
5.在巨噬细胞中,以LPS在不同时间梯度刺激细胞,用细胞免疫荧光的方法检测NF-κB的p65亚基的入核情况。结果证实,C15可以明显抑制LPS所导致的p65的入核情况,表明C15是通过阻止NF-κB的p65亚基入核,从而抑制相关炎症因子的表达,进而表现出一定的抗炎活性。
Resistin is a 114-amino-acid polypeptide which belongs to resistin-like molecule (RELM) family characterized by a highly conserved cysteine-rich C terminus. Recently, resistin has emerged as a novel pro-inflammatory factor. The association between resistin and inflammation has also been demonstrated in rheumatoid arthritis and other diseases, where resistin is capable of inducing vascular adhesion molecule expression and promoting leukocyte infiltration into tissues.
Two cyclooxygenease, COX-1 and COX-2, have been identified as the key enzymes regulating the production of prostaglandins. COX-2 is an inflammation-induced enzyme that remains undetectable in most mammalian tissues under basal conditions and is highly activated at the sites of inflammation. Some important pro-inflammatory cytokines, such as TNF-alpha, can also upregulate COX-2 expression via NF-kappa B pathway.
In this study, by choosing the important cytokine resistin and using real-time PCR, transfection and western blotting, we studied the regulation effect of COX-2 by resistin, and also researched the anti-inflammatory effect of chemerin-15 and got the following results:
1. Compared with controls, resistin remarkably upregulated COX-2 expression in RAW264.7 macrophage cells. Administration of anti-resistin antibody could reverse this effect.
2. Induction of COX-2 by resistin was markedly reduced in the presence of either dominant negative mutant IκBαor PDTC, a pharmacological inhibitor of NF-κB. NF-κB subunit p65 was also upregulated by resistin.
3. Moreover, we found that transforming growth factor-β-activated kinase 1 (TAK1), a mitogen-activated protein kinase kinase kinase (MAPKKK), could be activated in response to resistin.
4. Stimulated RAW cells with LPS, resistin and C15, measured the expression of COX-2 and iNOS. The results indicated that the inducing of COX-2 and iNOS could markedly reduced by C15.
5. We used macrophages as a model, using LPS as a proinflammatory substance representation measured the translocation of NF-κB subunit p65. The results indicated that the ranslocation of p65 induced by LPS could be obviously inhibited by C15. This result also proved the pecific mechanism of C15 generating antiinflammation.
引文
1. Adcock I M. (1997). Transcription factors as activators of gene transcription:AP-1 and NF-kappa B. Monaldi Arch Chest Dis,52:178-86
2. Al-Daghri N, Chetty R, McTernan P G, et al. (2005). Serum resistin is associated with c-reactive protein and LDL cholesterol in type 2 diabetes and coronary artery disease in a Saudi population. Cardiovasc Diabetol,4:10
3. Ali S, O'Boyle G, Mellor P, Kirby JA. (2007). An apparent paradox:chemokine receptor agonists can be used for anti-inflammatory therapy. Mol Immunol. 44(7):1477-82.
4. Arita M, Bianchini F, Aliberti J, Sher A, Chiang N, Hong S, Yang R, Petasis NA, Serhan CN. (2005). Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1.J Exp Med.201(5):713-22.
5. Arita M, Ohira T, Sun YP, Elangovan S, Chiang N, Serhan CN. (2007). Resolvin El selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation. J Immunol. 178(6):3912-7.
6. Bajaj M, Suraamornkul S, Hardies L J, Pratipanawatr T, DeFronzo R A. (2004). Plasma resistin concentration, hepatic fat content, and hepatic and peripheral insulin resistance in pioglitazone-treated type Ⅱ diabetic patients. Int J Obes Relat Metab Disord,28:783-789
7. Banerjee RR, Rangwala SM, Shapiro JS, Rich AS, Rhoades B, Qi Y, Wang J, Rajala MW, Pocai A, Scherer PE and others. (2004). Regulation of fasted blood glucose by resistin. Science,303(5661):1195-8
8. Barnea G, Strapps W, Herrada G, Berman Y, Ong J, Kloss B, Axel R, Lee KJ. (2008). The genetic design of signaling cascades to record receptor activation. ProcNatl Acad Sci USA.105(1):
9. Bastard JP, Jardel C, Bruckert E, Blondy P, Capeau J, Laville M, Vidal H, Hainque B. (2000). Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. J Clin Endocrinol Metab,85(9):3338-42
10. Bokarewa M, Nagaev I, Dahlberg L, et al. (2005). Resistin, an adipokine with potent pro-inflammatory properties. J Immunol,174:5789-5795
11. Bouloumie A, Sengenes C, Portolan G, Galitzky J, Lafontan M. (2001). Adipocyte produces matrix metalloproteinases 2 and 9:involvement in adipose differentiation. Diabetes,50(9):2080-6
12. Busmann A, Walden M, Wendland M, Kutzleb C, Forssmann WG, John H. (2004). A three-step purification strategy for isolation of hamster TIG2 from CHO cells: characterization of two processed endogenous forms. J Chromatogr B Analyt Technol Biomed Life Sci.811(2):217-23.
13. Cash JL, Hart R, Russ A, Dixon JP, Colledge WH, Doran J, Hendrick AG, Carlton MB, Greaves DR. (2008). Synthetic chemerin-derived peptides suppress inflammation through ChemR23. J Exp Med.205(4):767-75.
14. Charriere G, Cousin B, Arnaud E, Andre M, Bacou F, Penicaud L, Casteilla L. (2003). Preadipocyte conversion to macrophage. Evidence of plasticity. JBiol Chem,278(11): 9850-5
15. Chen J, Wang L, Boeg YS, Xia B, Wang J. (2002). Differential dimerization and association among resistin family proteins with implications for functional specificity. JEndocrinol,175(2):499-504
16. Cheung, P. C. F., Campbell, D. G., Nebreda, A. R., and Cohen, P. (2003). Feedback control of the protein kinase TAK1 by SAPK2a/p38alpha. EMBO J.22,5793-5805
17. Christiansen, T., Richelsen, B., and Bruun, J.M. (2005). Monocyte chemoattractant protein-1 is produced in isolated adipocytes, associated with adiposity and reduced after weight loss in morbid obese subjects. International journal of obesity.29, 146-150.
18. Chung SS, Choi HH, Cho YM, Lee HK, Park KS. (2006). Sp1 mediates repression of the resistin gene by PPARgamma agonists in 3T3-L1 adipocytes. Biochem Biophys Res Commun,348(1):253-8
19. Cousin B, Munoz O, Andre M, Fontanilles AM, Dani C, Cousin JL, Laharrague P, Casteilla L, Penicaud L. (1999). A role for preadipocytes as macrophage-like cells. Faseb J,13(2):305-12
20. Dai MH, Xia T, Chen XD, Gan L, Feng SQ, Qiu H, Peng Y, Yang ZQ. (2006). Cloning and characterization of porcine resistin gene. Domest Anim Endocrinol. Feb; 30(2):88-97.
21. David Bishop-Bailey, Jane A. Mitchell, Timothy D. Warner. (2006). COX-2 in Cardiovascular Disease. Arterioscler Thromb Vasc Biol.26:956-958.
22. Degawa-Yamauchi M, Bovenkerk J E, Juliar B E, Watson W, Kerr K, Jones R, Zhu Q, Considine R V. (2003). Serum resistin (FIZZ3) protein is increased in obese humans. J Clin Endocrinol Metab,88:5452-5455
23. Fehmann H C, Heyn J. (2002). Plasma resistin levels in patients with type 1 and type 2 diabetes mellitus and in healthy controls. Horm Metab Res,34:671-673
24. Fernandez-Real, J.M., and Ricart, W. (2003). Insulin resistance and chronic cardiovascular inflammatory syndrome. Endocrine reviews 24,278-301.
25. Festa, A., D'Agostino, R., Jr., Williams, K., Karter, A.J., Mayer-Davis, E.J., Tracy, R.P., and Haffner, S.M. (2001). The relation of body fat mass and distribution to markers of chronic inflammation. Int J Obes Relat Metab Disord 25,1407-1415.
26. Filippidis G, Liakopoulos V, Mertens P R, et al. (2005). Resistin serum levels are increased but not correlated with insulin resistance in chronic hemodialysis patients. Blood Purif,23:421-428
27. Fujinami A, Obayashi H, Ohta K, Ichimura T, Nishimura M, Matsui H, Kawahara Y, Yamazaki M, Ogata M, Hasegawa G, Nakamura N, Yoshikawa T, Nakano K, Ohta M. (2004). Enzyme-linked immunosorbent assay for circulating human resistin:resistin concentrations in normal subjects and patients with type 2 diabetes. Clin Chim Acta, 339:57-63
28. Fukui Y, Motojima K. (2002). Expression of resistin in the adipose tissue is modulated by various factors including peroxisome proliferator-activated receptor alpha. Diabetes Obes Metab,4:342-345
29. Gabriely I, Ma X H, Yang X M, Atzmon G, Rajala M W, Berg A H, Scherer P, Rossetti L. Barzilai N. (2002). Removal of visceral fat prevents insulin resistance and glucose intolerance of aging:an adipokine-mediated process? Diabetes,51:2951-2958
30. Galligan, C. L., Matsuyama, W.Matsukawa, A.,Mizuta, H.,Hodge, D. R.,Howard, O. M., Yoshimura, T., Up-Regulated (2004). Expression and Activation of the Orphan Chemokine Receptor, CCRL2, in Rheumatoid Arthritis. ARTHRITIS & RHEUMATISM.; 50(6):1806-1814
31. Gerber M, Boettner A, Seidel B, Lammert A, Bar J, Schuster E, Thiery J, Kiess W, Kratzsch J. (2005). Serum resistin levels of obese and lean children and adolescents: biochemical analysis and clinical relevance. J Clin Endocrinol Metab,90(8):4503-9
32. Gerstmayer B, Kusters D, Gebel S, et al. (2003). Identification of RELM-gamma, a novel resistin-like molecule with a distinct expression pattern. Genomics,81:588-595
33. Ghosh S, Singh A K, Aruna B, Mukhopadhyay S, Ehtesham N Z. (2003). The genomic organization of mouse resistin reveals major differences from the human resistin: functional implications. Gene,305:27-34
34. Giannopoulou I, Fernhall B, Carhart R, Weinstock R S, Baynard T, Figueroa A, Kanaley J A. (2005). Effects of diet and/or exercise on the adipocytokine and inflammatory cytokine levels of postmenopausal women with type 2 diabetes. Metabolism,54:866-875
35.Graveleau C, Zaha VG, Mohajer A, Banerjee RR, Dudley-Rucker N, Steppan CM, Rajala MW, Scherer PE, Ahima RS, Lazar MA and others. (2005). Mouse and human resistins impair glucose transport in primary mouse cardiomyocytes, and oligomerization is required for this biological action. JBiol Chem,280(36):31679-85
36. Groosman CG, Wiseman J, Lueas FS, et al. (1995). Inhibition of COX1 and COX2 in human platelets and mononuclear cells by NSAIDs. Inflamm Res.44(suppl.3):S272
37. Gui Y, Silha JV, Murphy LJ. (2004). Sexual dimorphism and regulation of resistin, adiponectin, and leptin expression in the mouse. Obes Res,12(9):1481-91
38. Guillabert A, Wittamer V, Bondue B, Godot V, Imbault V, Parmentier M, Communi D. (2008). Role of neutrophil proteinase 3 and mast cell chymase in chemerin proteolytic regulation. JLeukoc Biol. Aug 27.
39. Hartman HB, Hu X, Tyler KX, Dalal CK, Lazar MA. (2002). Mechanisms regulating adipocyte expression of resistin. JBiol Chem,277(22):19754-61
40. Haugen F, Jorgensen A, Drevon C A, Trayhurn P. (2001). Inhibition by insulin of resistin gene expression in 3T3-L1 adipocytes. FEBS Lett,507:105-108
41. Hehner, S. P., Hofmann, T. G., Ushmorov, A., Dienz, O., Wing-Lan Leung, I., Lassam, N., Scheidereit, C., Droge, W., and Schmitz, M. L. (2000). Mixed-lineage kinase 3 delivers CD3/CD28-derived signals into the IkappaB kinase complex. Mol. Cell. Biol. 20,2556-2568
42. Heilbronn LK, Rood J, Janderova L, Albu JB, Kelley DE, Ravussin E, Smith SR. (2004). Relationship between serum resistin concentrations and insulin resistance in nonobese, obese, and obese diabetic subjects. J Clin Endocrinol Metab,89(4):1844-8
43. Holcomb I N, Kabakoff R C, Chan B, Baker T W, Gurney A, Henzel W, Nelson C, Lowman H B, Wright B D, Skelton N J, Frantz G D, Tumas D B, Peale F V, Jr. Shelton D L Hebert C C. (2000). FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. Embo J,19:4046-4055
44. Hotamisligil GS, Shargill NS, Spiegelman BM. (1993). Adipose expression of tumor necrosis factor-alpha:direct role in obesity-linked insulin resistance. Science, 259(5091):87-91
45. Iqbal N, Seshadri P, Stern L, et al. (2005). Serum resistin is not associated with obesity or insulin resistance in humans. Eur Rev Med Pharmacol Sci,9:161-165
46. Ishitani, T., Takaesu, G., Ninomiya-Tsuji, J., Shibuya, H., Gaynor, R. B., and Matsumoto, K. (2003). Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling. EMBOJ.22,6277-6288
47. Janke J, Engeli S, Gorzelniak K, Luft F C, Sharma A M. (2002). Resistin gene expression in human adipocytes is not related to insulin resistance. Obes Res,10:1-5
48. John H, Hierer J, Haas O, Forssmann WG. (2007). Quantification of angiotensin-converting-enzyme-mediated degradation of human Chemerin 145-154 in plasma by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry. Anal Biochem.362(1):117-25.
49. Johnson, G. L., and Lapadat, R. (2002). Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298,1911-1912
50. Juan C C, Au L C, Fang V S, Kang S F, Ko Y H, Kuo S F, Hsu Y P, Kwok C F, Ho L T. (2001). Suppressed gene expression of adipocyte resistin in an insulin-resistant rat model probably by elevated free fatty acids. Biochem Biophys Res Commun,289: 1328-1333
51. Kaser S, Kaser A, Sandhofer A, et al. (2003). Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro. Biochem Biophys Res Commun 309:286-290
52. Kawanami D, Maemura K, Takeda N, Harada T, Nojiri T. (2004). Direct reciprocal effects of resistin and adiponectin on vascular endothelial cells:a new insight into adipocytokine-endothelial cell interactions. Biochem Biophys Res Commun 314:415-419
53. Kershaw, E.E., and Flier, J.S. (2004). Adipose tissue as an endocrine organ. The Journal of clinical endocrinology and metabolism 89,2548-2556.
54. Kim K H, Lee k Moon Y S, et al. (2001). A cysteine-rich adipose tissue-specific secretory factor inhibits adipocyte differentiation. JBiol Chem,276:11252-11256
55. Kulig P, Zabel BA, Dubin G, Allen SJ, Ohyama T, Potempa J, Handel TM, Butcher EC, Cichy J. (2007). Staphylococcus aureus-derived staphopain B, a potent cysteine protease activator of plasma Chemerin. J Immunol.178(6):3713-20
56. Kusminski CM, McTernan PG, Kumar S. (2005). Role of resistin in obesity, insulin resistance and Type Ⅱ diabetes. Clin Sci (Lond),109(3):243-56
57. Kyriakis, J. M., and Avruch, J. (2001). Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol. Rev.81, 807-869
58. Lande R, Gafa V, Serafini B, Giacomini E, Visconti A, Remoli ME, Severa M, Parmentier M, Ristori G, Salvetti M, Aloisi F, Coccia EM. (2008). Plasmacytoid dendritic cells in multiple sclerosis:intracerebral recruitment and impaired maturation in response to interferon-beta. JNeuropathol Exp Neurol.67(5):388-401
59. Lang CH, Dobrescu C, Bagby GJ. (1992). Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output. Endocrinology,130(1): 43-52
60. Le Lay S, Boucher J, Rey A, Castan-Laurell I, Krief S, Ferre P, Valet P, Dugail I. (2001). Decreased resistin expression in mice with different sensitivities to a high-fat diet. Biochem Biophys Res Commun,289:564-567
61. Lee J H, Chan J L, Yiannakouris N, et al. (2003). Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration:cross-sectional and interventional studies in normal, insulin-resistant, and diabetic subjects. J Clin Endocrinol Metab,88:4848-4856
62. Lu S C, Shieh W Y, Chen C Y, Hsu S C, Chen H L. (2003). Lipopolysaccharide increases resistin gene expression in vivo and in vitro. FEBS Lett,530:158-162
63. Makimura H, Mizuno T M, Bergen H, Mobbs C V. (2002). Adiponectin is stimulated by adrenalectomy in ob/ob mice and is highly correlated with resistin mRNA. Am J Physiol Endocrinol Metab,283:E1266-71
64. Makowski L, Boord JB, Maeda K, Babaev VR, Uysal KT, Morgan MA, Parker RA, Suttles J, Fazio S, Hotamisligil GS and others. (2001). Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis. Nat Med,7(6):699-705
65. McTernan P G, Fisher F M, Valsamakis G, Chetty R, Harte A, McTernan C L, Clark P M, Smith S A., Barnett A H, Kumar S. (2003). Resistin and type 2 diabetes:regulation of resistin expression by insulin and rosiglitazone and the effects of recombinant resistin on lipid and glucose metabolism in human differentiated adipocytes. J Clin Endocrinol Metab,88:6098-6106.
66. McTernan P G, McTernan C L, Chetty R, Jenner K, Fisher F M., Lauer M N, Crocker J, Barnett A H, Kumar S. (2002). Increased resistin gene and protein expression in human abdominal adipose tissue. J Clin Endocrinol Metab,87:2407
67. Meder W, Wendland M, Busmann A, Kutzleb C, Spodsberg N, John H, Richter R, Schleuder D, Meyer M, Forssmann WG. (2003). Characterization of human circulating TIG2 as a ligand for the orphan receptor ChemR23. FEBS Lett.555(3):495-9
68. Migita K, Maeda Y, Miyashita T. (2006). The serum levels of resistin in rheumatoid arthritis patients. Clinical and Experimental Rheumatology 24:698-701.
69. Milan G, Granzotto M, Scarda A, Calcagno A, Pagano C, Federspil G, Vettor R. (2002). Resistin and adiponectin expression in visceral fat of obese rats:effect of weight loss. Obes Res,10:1095-1103
70.-Minn A H, Patterson N B, Pack S, Hoffmann S C, Gavrilova O, Vinson C, Harlan D M, Shalev A. (2003). Resistin is expressed in pancreatic islets. Biochem Biophys Res Commun,310:641-645
71. Mohamed-Ali V, Goodrick S, Bulmer K, Holly JM, Yudkin JS, Coppack SW. (1999). Production of soluble tumor necrosis factor receptors by human subcutaneous adipose tissue in vivo. Am JPhysiol,277(6 Pt 1):E971-5
72. Moller DE. (2000). Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol Metab,11(6):212-7
73. Moon B, Kwan JJ, Duddy N, Sweeney G, Begum N. (2003). Resistin inhibits glucose uptake in L6 cells independently of changes in insulin signaling and GLUT4 translocation. Am J Physiol Endocrinol Metab,285(1):E106-15
74. Moore G B, Chapman H, Holder J C, Lister C A, Piercy V, Smith S A, Clapham J C. (2001). Differential regulation of adipocytokine mRNAs by rosiglitazone in db/db mice. Biochem Biophys Res Commun 286:735-741
75. Moretta A, Marcenaro E, Parolini S, Ferlazzo G and Moretta L. (2007). NK cells at the interface between innate and adaptive immunity.Cell Death and Differentiation 1-8
76. Morrison RF, Farmer SR. (2000). Hormonal signaling and transcriptional control of adipocyte differentiation. JNutr,130(12):3116S-3121S
77. Movat, H.Z., and M.I. Cybulsky. (1987). Neutrophil emigration and microvascular injury. Role of chemotaxins, endotoxin, interleukin-1 and tumor necrosis factor alpha. Pathol. Immunopathol. Res.6:153-176.
78. Movat, H.Z., M.I. Cybulsky, I.G. Colditz, M.K. Chan, and C.A. Dinarello. (1987). Acute infl ammation in gram-negative infection:endotoxin, interleukin 1, tumor necrosis factor, and neutrophils. Fed. Proc.46:97-104.
79. Nagaev I, Smith U. (2001). Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle. Biochem Biophys Res Commun,285:561-564
80. Nogueiras R, Gallego R, Gualillo O, Caminos JE, Garcia-Caballero T, Casanueva FF, Dieguez C. (2003a). Resistin is expressed in different rat tissues and is regulated in a tissue-and gender-specific manner. FEBS Lett,548(1-3):21-7
81. Nogueiras R, Gualillo 0, Caminos JE, Casanueva FF, Dieguez C. (2003b). Regulation of resistin by gonadal, thyroid hormone, and nutritional status. Obes Res,11(3): 408-14
82. Patel L, Buckels A C, Kinghorn IJ, et al. (2003). Resistin is expressed in human macrophages and directly regulated by PPAR gamma activators. Biochem Biophys Res Commun,300:472-476
83. Patel SD, Rajala MW, Rossetti L, Scherer PE, Shapiro L. (2004). Disulfide-dependent multimeric assembly of resistin family hormones. Science,304(5674):1154-8
84. Pfutzner A, Langenfeld M, Kunt T, Lobig M, Forst T. (2003). Evaluation of human resistin assays with serum from patients with type 2 diabetes and different degrees of insulin resistance. Clin Lab,49:571-576
85. Pischon T, Bamberger C M, Kratzsch J, Zyriax B C, Algenstaedt P, Boeing H, Windler E:(2005). Association of plasma resistin levels with coronary heart disease in women. Obes Res,13:1764-1771
86. Rajala M W, Lin Y, Ranalletta M, Yang X M, Qian H, Gingerich R, Barzilai N, Scherer P E. (2002). Cell type-specific expression and coregulation of murine resistin and resistin-like molecule-alpha in adipose tissue. Mol Endocrinol,16:1920-1930
87. Rajala M W, Qi Y, Patel H R, Takahashi N, Banerjee R, Pajvani U B, Sinha M K, Gingerich R L, Scherer P E, Ahima R S. (2004). Regulation of resistin expression and circulating levels in obesity, diabetes, and fasting. Diabetes,53:1671-1679
88. Rajala MW, Obici S, Scherer PE, Rossetti L. (2003). Adipose-derived resistin and gut-derived resistin-like molecule-beta selectively impair insulin action on glucose production. J Clin Invest,111(2):225-30
89. Rajala, M.W., and Scherer, P.E. (2003). Minireview:The adipocyte--at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology 144, 3765-3773.
90. Rangwala SM, Rich AS, Rhoades B, Shapiro JS, Obici S, Rossetti L, Lazar MA. (2004). Abnormal glucose homeostasis due to chronic hyperresistinemia. Diabetes, 53(8):1937-41
91. Rasouli N, Yao-Borengasser A, Miles L M, Elbein S C, Kern P A. (2006). Increased plasma adiponectin in response to pioglitazone does not result from increased gene expression. Am J Physiol Endocrinol Metab,290:E42-E46
92. Rea R, Donnelly R. (2006). Effects of metformin and oleic acid on adipocyte expression of resistin. Diabetes Obes Metab,8:105-109
93. Reilly M P, Lehrke M, Wolfe M L, Rohatgi A, Lazar M A, Rader D J. (2005). Resistin is an inflammatory marker of atherosclerosis in humans. Circulation,111:932-939
94. Reinehr T, Roth C L, Menke T, Andler W. (2006). Resistin concentrations before and after weight loss in obese children. Int J Obes (Lond),30:297-301
95. Samson, M., Edinger, A.L., Stordeur, P., Rucker, J., Verhasselt, V., Sharron,M., Govaerts, C., Mollereau, C., Vassart, G., Doms, R.W., Parmentier, M. (1998). ChemR23, a putative chemoattractant receptor, is expressed in monocyte-derived dendritic cells and macrophages and is a coreceptor for SIV and some primary HIV-1 strains. Eur. J. Immunol.28,1689-1700.
96. Savage D B, Sewter C P, Klenk E S, Segal D G, Vidal-Puig A, Considine R V, O'Rahilly S. (2001). Resistin/Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans. Diabetes,50:2199-2202
97. Schaffler A, Buchler C, Muller-Ladner U, Herfarth H, Ehling A, Paul G, Scholmerich J, Zietz B. (2004). Identification of variables influencing resistin serum levels in patients with type 1 and type 2 diabetes mellitus. Horm Metab Res,36(10):702-7
98. Schreyer SA, Chua SC, Jr., LeBoeuf RC. (1998). Obesity and diabetes in TNF-alpha receptor-deficient mice. J Clin Invest,102(2):402-11
99. Sen R. Baltimore D. (1986). Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell,46:705-716
100.Senolt L, Housa D, Vernerova Z. (2007). Resistin in rheumatoid arthritis synovial tissue, synovial fluid and serum. Annals of the Rheumatic Diseases 66:458-463.
101.Sentinelli F, Romeo S, Arca M, Filippi E, Leonetti F, Banchieri M, Di Mario U, Baroni M G. (2002). Human resistin gene, obesity, and type 2 diabetes:mutation analysis and population study. Diabetes,51:860-862
102.Shetty G K, Economides P A, Horton E S, et al. (2004). Circulating adiponectin and resistin levels in relation to metabolic factors, inflammatory markers, and vascular reactivity in diabetic patients and subjects at risk for diabetes. Diabetes Care, 27:2450-2457
103.Shimomura, I., Funahashi, T., Takahashi, M., Maeda, K., Kotani, K., Nakamura, T., Yamashita, S., Miura, M., Fukuda, Y, Takemura, K., et al (1996). Enhanced expression of PAI-1 in visceral fat:possible contributor to vascular disease in obesity. Nature medicine 2,800-803.
104.Shojima N, Sakoda H, Ogihara T, Fujishiro M, Katagiri H, Anai M, Onishi Y, Ono H, Inukai K, Abe M, Fukushima Y, Kikuchi M, Oka Y, Asano T. (2002). Humoral regulation of resistin expression in 3T3-L1 and mouse adipose cells. Diabetes,51: 1737-1744
105.Siegle I, Klein T.1998. Expression of cyclooxygenase 1 and cyclooxygenase 2 in human synovial tissue:differential elevation of cyclooxygenase 2 in inflammatory joint diseases. Arthritis & Rheumatism 41:122-129.
106.Silha J V, Krsek M, Skrha J V, Sucharda P, Nyomba B L, Murphy L J. (2003). Plasma resistin, adiponectin and leptin levels in lean and obese subjects:correlations with insulin resistance. Eur J Endocrinol,149:331-335
107.Silswal N, Singh A K, Aruna B, et al. (2005). Human resistin stimulates the proinflammatory cytokines TNF-alpha and IL-12 in macrophages by NFkappaB-dependent pathway. Biochem Biophys Res Commun,334:1092-1101
108.Simon LS. (1999). Role and regulation of cyclooxygenase-2 during inflammation. Am J Med.106(5B):37S-42S
109.Soukas, A., Cohen, P., Socci, N.D., and Friedman, J.M. (2000). Leptin-specific patterns of gene expression in white adipose tissue. Genes & development 14,963-980.
110.Stejskal D, Adamovska S, Bartek J, et al. (2003). Resistin:concentrations in persons with type 2 diabetes mellitus and in individuals with acute inflammatory disease. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub,147:63-69
111.Stephens JM, Lee J, Pilch PF. (1997). Tumor necrosis factor-alpha-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction. J Biol Chem,272(2):971-6
112.Steppan C M, Bailey S T, Bhat S, et al. (2001a). The hormone resistin links obesity to diabetes. Nature,409:307-312
113.Steppan C M, Brown E J, Wright C M, et al. (2001b). A family of tissue-specific resistinlike molecules. Proc Natl Acad Sci USA,98:502-506
114.Steppan C M, Lazar M A. (2002). Resistin and obesity-associated insulin resistance. Trends Endocrinol Metab,13:18-23
115.Steppan C M, Wang J, Whiteman E L, Birnbaum M J, Lazar M A. (2005). Activation of SOCS-3 by resistin. Mol Cell Biol,25:1569-1575
116.Takaesu, G., Surabhi, R. M., Park, K. J., Ninomiya-Tsuji, J., Matsumoto, K., and Gaynor, R. B. (2003). TAK1 is critical for IkappaB kinase-mediated activation of the NF-kappaB pathway. J. Mol. Biol. 326,105-115
117.Takahashi, K., Mizuarai, S., Araki, H., Mashiko, S., Ishihara, A., Kanatani, A., Itadani, H., and Kotani, H. (2003). Adiposity elevates plasma MCP-1 levels leading to the increased CD11b-positive monocytes in mice. The Journal of biological chemistry 278, 46654-46660.
118.Takahashi, M. Takahashi, Y. Takahashi, K. Zolotaryov, F. N. Hong, K. S. Kitazawa, R. Iida, K. Okimura, Y. Kaji, H. Kitazawa, S. Kasuga, M. Chihara, K. (2008). Chemerin enhances insulin signaling and potentiates insulin-stimulated glucose uptake in 3T3-L1 adipocytes. FEBS Lett;582(5):573-8
119.Tamura, S., Hanada, M., Ohnishi, M., Katsura, K., Sasaki, M., and Kobayashi, T. (2002). Regulation of stress-activated protein kinase signaling pathways by protein phosphatases. Eur. J. Biochem.269,1060-1066
120.Tontonoz P, Nagy L, Alvarez JG, Thomazy VA, Evans RM. (1998). PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell, 93(2):241-52
121.Trayhurn, P., and Wood, I.S. (2004). Adipokines:inflammation and the pleiotropic role of white adipose tissue. The British journal of nutrition 92,347-355.
122.Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. (1997). Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature, 389(6651):610-4
123.Vane JR. (1994).Towards a better aspirin. Nature,36(2):215-216.
124.Vermi W, Riboldi E, Wittamer V, et al. (2005). Role of ChemR23 in directing the migration of myeloid and plasmacytoid dendritic cells to lymphoid organs and inflamed skin. J Exp Med 201:509-515
125.Vozarova de Courten B, Degawa-Yamauchi M, Considine R V, et al. (2004). High serum resistin is associated with an increase in adiposity but not a worsening of insulin resistance in Pima Indians. Diabetes,53:1279-1284
126. Way J M., Gorgun C Z, Tong Q, Uysal K T, Brown K K, Harrington W W, Oliver W R, Jr, Willson T M, Kliewer S A, Hotamisligil G S. (2001). Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists. J Biol Chem,276:25651-25653
127.Weisberg, S.P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R.L., and Ferrante, A.W., Jr. (2003). Obesity is associated with macrophage accumulation in adipose tissue. The Journal of clinical investigation 112,1796-1808.
128.Wellen, K.E., and Hotamisligil, G.S. (2003). Obesity-induced inflammatory changes in adipose tissue. The Journal of clinical investigation 112,1785-1788.
129.Wellen, K.E., and Hotamisligil, G.S. (2005). Inflammation, stress, and diabetes. The Journal of clinical investigation 115,1111-1119.
130.Wittamer V, Bondue B, Guillabert A, Vassart G, Parmentier M, Communi D. (2005). Neutrophil-Mediated Maturation of Chemerin:A Link between Innate and Adaptive Immunity. The Journal of Immunology,175:487-493
131.Wittamer V, Gregoire F, Robberecht P, Vassart G, Communi D, Parmentier M. (2004). The C-terminal nonapeptide of mature Chemerin activates the Chemerin receptor with low nanomolar potency. JBiol Chem.279(11):9956-62.
132.Wu D, Marko M, Claycombe K, Paulson KE and Meydani SN. (2003). Ceramide-induced and age-associated increase in macrophage COX-2 expression is mediated through up-regulation of NF-kappa B activity. Journal of Biological Chemistry 278:10983-10992.
133.Xarier Rabasseda. (1996). Nimesulide:a elective cyclooxygenae-2 inhibitor antiinflammatory drug. Drugs Today.32 (Suppl)D:S1-S23.
134.Xiao-Yan Du, Brian A. Zabel, Timothy Myles, Samantha J. Allen, Tracy M. Handel, Peter P. Lee, Eugene C. Butcher, and Lawrence L. Leung. (2008). Regulation of chemerin bioactivity by plasma carboxypeptidase N, carboxypeptidase B (TAFIa) and platelets. J. Biol. Chem. Papers In Press, published online ahead of print November 14.
135.Xu, H., Barnes, G.T., Yang, Q., Tan, G., Yang, D., Chou, C.J., Sole, J., Nichols, A., Ross, J.S., Tartaglia, L.A., and Chen, H. (2003). Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. The Journal of clinical investigation 112,1821-1830.
136.Yang, J., Lin, Y., Guo, Z., Cheng, J., Huang, J., Deng, L., Liao, W., Chen, Z., Liu, Z., and Su, B. (2001). The essential role of MEKK3 in TNF-induced NF-kappaB activation. Nat. Immunol.2,620-624
137. Yannakoulia M, Yiannakouris N, Bluher S, Matalas A L, Klimis-Zacas D, Mantzoros C S. (2003). Body fat mass and macronutrient intake in relation to circulating soluble leptin receptor, free leptin index, adiponectin, and resistin concentrations in healthy humans. J Clin Endocrinol Metab,88:1730-1736
138.Youn B S, Yu K Y, Park H J, Lee N S, Min S S, Youn M Y, Cho Y M, Park Y J, Kim S Y, Lee H K, Park K S. (2004). Plasma resistin concentrations measured by enzyme-linked immunosorbent assay using a newly developed monoclonal antibody are elevated in individuals with type 2 diabetes mellitus. J Clin Endocrinol Metab,89:150-156
139.Yudkin, J.S., Stehouwer, C.D., Emeis, J.J., and Coppack, S.W. (1999). C-reactive protein in healthy subjects:associations with obesity, insulin resistance, and endothelial dysfunction:a potential role for cytokines originating from adipose tissue? Arteriosclerosis, thrombosis, and vascular biology 19,972-978.
140.Yura S, Sagawa N, Itoh H, Kakui K, Nuamah M A, Korita D, Takemura M, Fujii S. (2003). Resistin is expressed in the human placenta. J Clin Endocrinol Metab,88: 1394-1397
141.Yurochko A D, Kowalik T F, Huong S M. (1995). Human Cytomegalovirus Upregulates NF-B Activity by Transactivating the NF-B p105/p50 and p65 Promoters. Journal of Virology, Sept,5391-5400
142.Zabel BA, Allen SJ, Kulig P, Allen JA, Cichy J, Handel TM, Butcher EC. (2005). Chemerin activation by serine proteases of the coagulation, fibrinolytic, and inflammatory cascades. JBiol Chem.280(41):34661-6.
143.Zabel BA, Allen SJ, Kulig P, Allen JA, Cichy J, Handel TM, Butcher EC. (2005). Chemerin activation by serine proteases of the coagulation, fibrinolytic, and inflammatory cascades. J Biol Chem.280(41):34661-6.
144.Zabel BA, Allen SJ, Kulig P, Allen JA, Cichy J, Handel TM, Butcher EC. (2005). Chemerin activation by serine proteases of the coagulation, fibrinolytic, and inflammatory cascades. J Biol Chem.280(41):34661-6.
145.Zabel BA, Nakae S, Zuniga L, Kim JY, Ohyama T, Alt C, Pan J, Suto H, Soler D, Allen SJ, Handel TM, Song CH, Galli SJ, Butcher EC. (2008). Mast cell-expressed orphan receptor CCRL2 binds chemerin and is required for optimal induction of IgE-mediated passive cutaneous anaphylaxis. JExp Med.205(10):2207-20.
146. Zabel BA, Zuniga L, Ohyama T, Allen SJ, Cichy J, Handel TM, Butcher EC. (2006). Chemoattractants, extracellular proteases, and the integrated host defense response. Exp Hematol.34(8):1021-32.