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系統識別號 U0026-0608201414001200
論文名稱(中文) 白血球細胞訊息傳遞在肥胖引起繼發型免疫不全症所扮演之角色
論文名稱(英文) The Role of Leukocyte Signal Transduction on the Pathogenesis of Secondary Immunodeficiency in Obesity
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 102
學期 2
出版年 103
研究生(中文) 顏嘉良
研究生(英文) Chia-Liang Yen
學號 S58961400
學位類別 博士
語文別 英文
論文頁數 95頁
口試委員 指導教授-謝奇璋
召集委員-蔡少正
口試委員-林以行
口試委員-葉才明
口試委員-蔡曜聲
口試委員-許秉寧
口試委員-張堯
口試委員-齊嘉鈺
中文關鍵字 肥胖  繼發型免疫缺損  自然免疫  細胞激素 
英文關鍵字 Obesity  Innate immunity  Cytokines  Immunodeficiency Diseases 
學科別分類
中文摘要   肥胖可能導致第二型糖尿病以及心血管疾病等併發症,為世界上重要的公衛健康問題之一。免疫細胞的活化以及全身性的慢性發炎,已知是肥胖引起併發症的重要致病機轉。但是同時,研究指出肥胖患者有免疫力低下並且較容易受到感染的現象。此現象與肥胖患者體內免疫系統較為活化的現象相牴觸。因此,本研究想要藉由研究肥胖患者的白血球在受到 Toll-like receptor (TLR) 刺激之後產生細胞激素的反應,來了解造成肥胖患者免疫力低下的致病機轉。我們發現到肥胖患者的全血細胞在經由 TLR 刺激劑刺激之後所產生的促發炎細胞激素包括 gamma型干擾素、介白素 (interleukin, IL)-6 以及腫瘤壞死因子明顯少於健康對照組,而抑制性細胞激素 IL-10 的產量則有顯著的提升。肥胖患者周邊血單核球 (peripheral blood mononuclear cells, PBMCs) 中的肝醣合成酶激酶-3β (glycogen synthase kinase-3β, GSK-3β) 有較高的磷酸化程度。同時,胰島素或是脂多糖 (lipopolysaccharide, LPS) 的刺激無法促進肥胖患者 PBMC 中 GSK-3β 進一步的磷酸化。另外,我們發現到 LPS 刺激肥胖患者 PBMC所引起的 IκB 降解也較健康受試者低下。為了瞭解這些現象的分子機轉,我們抑制人類單核球細胞株 THP-1 中 GSK-3β 的表現,或是將細胞培養於高胰島素以及高游離脂肪酸的環境,研究細胞在模擬肥胖環境中受到 LPS 刺激後促進發炎的轉錄因子 NF-κB 以及抑制發炎的的轉錄因子 cAMP response element-binding protein (CREB) 的反應。我們發現處於模擬肥胖環境之 THP-1 細胞受到 LPS 刺激後,NF-κB 活化的程度有明顯下降。同時CREB 的活性有明顯的增強。在後續追蹤實驗中,我們發現肥胖患者在經過減重手術後,上述細胞激素分泌能力缺損的現象有明顯的改善。我們另外發現到可能由代謝不正常的肥胖所引起之第二型糖尿病病患也有類似於肥胖病患的不正常先天性免疫反應。經由本研究,我們得知肥胖引起的不正常代謝在第二型糖尿病發病之前,會因為GSK-3β 的過度磷酸化而影響免疫細胞在感染的情況下細胞激素之產生,造成自然免疫反應的繼發型缺損。
英文摘要 Obesity is a severe health problem worldwide which leads to multiple comorbidities including type 2 diabetes mellitus (DM) and cardiovascular diseases. Inflammation has been found to be an important characteristic of adipose tissue in obese subjects. However, obesity is also associated with compromised immune responses to infections and the impact of obesity on immune function has not been fully understood. To clarify the role of obesity in the immune responses, I investigated the Toll-like receptor (TLR)-induced cytokine secretion by leukocytes from obese and lean subjects. The relationship between insulin-induced intracellular signaling and cytokine production using peripheral blood mononuclear cells (PBMC) and a monocytic cell line THP-1 was also investigated. I found decreased TLR-induced interferon-gamma, interleukin-6 and tumor necrosis factor-alpha secretions and elevated IL-10 secretion by leukocytes from obese subjects when compared with those in lean controls. PBMCs from obese subjects showed enhanced basal Akt and glycogen synthase kinase 3β (GSK-3β) phosphorylation which did not further increased with insulin and lipopolysaccharide (LPS) stimulation. I also found that LPS-induced IκB degradation was inhibited in PBMCs from obese subjects. By using THP-1 cells with GSK-3β knockdown or cells treated with hyperinsulinemic and high fatty acid conditions, I found that LPS-induced NF-κB activation was inhibited and cAMP response element-binding protein (CREB) activation was enhanced. I also found that bariatric surgery corrected the abnormal TLR-induced cytokine secretions in obese subjects. Moreover, type 2 DM, which may be developed from obesity, also showed abnormal TLR-induced cytokine secretions. These findings indicated that GSK-3β is important in the regulation of NF-κB and CREB activation in leukocytes under the metabolic condition of obesity. Our study hence reveals a key mechanism through which metabolic abnormalities, even before the onset of type 2 DM, compromise leukocyte functions in people with obesity.
論文目次 中文摘要 I
Abstract III
誌謝 V
Table of contents VI
Figure list IX
Table list XI
Abbreviations XII
Chapter 1: Introduction 1
1-1 The paradox: chronic immune activation and susceptibility to infections in obesity 3
1-1-1 The characteristic metabolic abnormality in obesity 3
1-1-2 Chronic inflammation in obesity 4
1-1-3 Aberrant leukocyte responses and increased incidence of infection in obesity 7
1-1-4 Secondary immunodeficiency in type 2 DM. 9
1-1-5 Weight loss interventions reduce abnormal immune conditions in obesity 11
1-2 Innate immune defense against infections 13
1-2-1 TLR-induced cytokine secretion 13
1-2-2 NADPH oxidase-induced ROS production 14
1-2-3 Regulation of innate immunity by GSK-3β and IL-10 16
1-3 The complex interaction between obesity and immunity 19
Chapter 2: Objective of this study 20
Chapter 3: Materials and methods 21
3-1 Subjects of lean and obese groups 21
3-2 Reagents and antibodies 22
3-3 TLR-induced cytokine secretion by stimulated blood cells 22
3-4 PBMCs preparation and treatment 23
3-5 BSA-Palmitate preparation 24
3-6 Cell culture and treatment 24
3-7 ROS production measured by Chemiluminescence 25
3-8 ROS production measured by flow cytometry 25
3-9 SDS-PAGE and Western blot analysis 26
3-10 Lentiviral targeting GSK-3 for gene knockdown 26
3-11 Immunofluorescence analysis 27
3-12 Chromatin immunoprecipitation (ChIP) 27
3-13 Statistics 29
Chapter 4: Phosphorylation of GSK-3β in metabolically abnormal obesity affects immune stimulation-induced cytokine production 30
4-1 Demographic and clinical characteristics of the lean and obese study groups 30
4-2 Decreased IFN-gamma, IL-6, TNF-alfa and increased IL-10 secretion by TLR-stimulated whole blood samples from obese subjects 34
4-3 Correlation between TLR-induced IL-6 and IL-10 secretion with BMI and serum insulin concentration 36
4-4 Mononuclear leukocytes of obese subjects had elevated basal Akt and GSK-3β phosphorylation which did not further increase after insulin and LPS stimulation 39
4-5 Decrease in LPS-induced IκB degradation in PBMCs of obese subjects and in monocytic cells treated with high-insulin and high-free fatty acid conditions 43
4-6 Inhibition of GSK-3β decreased LPS-induced NF-kB activation but increased CREB activation 46
4-7 Basal phosphorylated GSK-3β level was enhanced in splenocytes of ob/ob mice. 55
4-8 Discussion 56
Chapter 5: Innate immune functions in obese subjects with bariatric surgery and in subjects with type 2 DM 61
5-1 Bariatric surgery corrected TLR-induced cytokine secretions of obese subjects 61
5-2 Whole blood leukocytes isolated from type 2 DM patients had lower cytokine production ability compared with control subjects 65
5-3 High glucose conditions inhibited PMA-induced ROS production in differentiated HL-60 cells. 69
5-4 There were no differences in granulocyte ROS production between lean and obese subjects 70
5-5 Discussion 71
Chapter 6: Conclusion and perspectives 74
Reference List 77
Curriculum Vitae 94
參考文獻 1. Finkelstein EA, Khavjou OA, Thompson H, Trogdon JG, Pan L, Sherry B, et al. Obesity and severe obesity forecasts through 2030. Am J Prev Med 2012, 42(6): 563-570.

2. Reaven G, Abbasi F, McLaughlin T. Obesity, insulin resistance, and cardiovascular disease. Recent Prog Horm Res 2004, 59: 207-223.

3. WHO. Obesity and Overweight. Geneva: World Health Organisation. 2014 [cited]Available from: http://www.who.int/mediacentre/factsheets/fs311/en

4. Lumeng CN. Innate immune activation in obesity. Mol Aspects Med 2013, 34(1): 12-29.

5. Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature 2006, 444(7121): 881-887.

6. Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 2006, 444(7121): 840-846.

7. Huttunen R, Syrjanen J. Obesity and the risk and outcome of infection. Int J Obes (Lond) 2013, 37(3): 333-340.

8. Mittelman SD, Van Citters GW, Kirkman EL, Bergman RN. Extreme insulin resistance of the central adipose depot in vivo. Diabetes 2002, 51(3): 755-761.

9. Despres JP. Is visceral obesity the cause of the metabolic syndrome? Ann Med 2006, 38(1): 52-63.

10. Galic S, Oakhill JS, Steinberg GR. Adipose tissue as an endocrine organ. Mol Cell Endocrinol 2010, 316(2): 129-139.

11. Fantuzzi G. Adipose tissue, adipokines, and inflammation. J Allergy Clin Immunol 2005, 115(5): 911-919; quiz 920.

12. Odegaard JI, Chawla A. Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis. Science 2013, 339(6116): 172-177.

13. Eldar-Finkelman H, Schreyer SA, Shinohara MM, LeBoeuf RC, Krebs EG. Increased glycogen synthase kinase-3 activity in diabetes- and obesity-prone C57BL/6J mice. Diabetes 1999, 48(8): 1662-1666.

14. Dey D, Basu D, Roy SS, Bandyopadhyay A, Bhattacharya S. Involvement of novel PKC isoforms in FFA induced defects in insulin signaling. Mol Cell Endocrinol 2006, 246(1-2): 60-64.

15. Nieto-Vazquez I, Fernandez-Veledo S, Kramer DK, Vila-Bedmar R, Garcia-Guerra L, Lorenzo M. Insulin resistance associated to obesity: the link TNF-alpha. Arch Physiol Biochem 2008, 114(3): 183-194.

16. Maedler K, Dharmadhikari G, Schumann DM, Storling J. Interleukin-1 beta targeted therapy for type 2 diabetes. Expert Opin Biol Ther 2009, 9(9): 1177-1188.

17. Ahmad R, Al-Mass A, Atizado V, Al-Hubail A, Al-Ghimlas F, Al-Arouj M, et al. Elevated expression of the toll like receptors 2 and 4 in obese individuals: its significance for obesity-induced inflammation. J Inflamm (Lond) 2012, 9(1): 48.

18. Dasu MR, Jialal I. Free fatty acids in the presence of high glucose amplify monocyte inflammation via Toll-like receptors. Am J Physiol Endocrinol Metab 2011, 300(1): E145-154.

19. Wong SW, Kwon MJ, Choi AM, Kim HP, Nakahira K, Hwang DH. Fatty acids modulate Toll-like receptor 4 activation through regulation of receptor dimerization and recruitment into lipid rafts in a reactive oxygen species-dependent manner. J Biol Chem 2009, 284(40): 27384-27392.

20. Glass CK, Olefsky JM. Inflammation and lipid signaling in the etiology of insulin resistance. Cell Metab 2012, 15(5): 635-645.

21. Himes RW, Smith CW. Tlr2 is critical for diet-induced metabolic syndrome in a murine model. FASEB J 2010, 24, 731-739.

22. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 2006, 116(11): 3015-3025.

23. Stienstra R, Tack CJ, Kanneganti TD, Joosten LA, Netea MG. The inflammasome puts obesity in the danger zone. Cell Metab 2012, 15(1): 10-18.

24. Dinarello CA. A clinical perspective of IL-1beta as the gatekeeper of inflammation. Eur J Immunol 2011, 41(5): 1203-1217.

25. Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 2011, 17(2): 179-188.

26. Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol 2011, 12(5): 408-415.

27. Dixon LJ, Flask CA, Papouchado BG, Feldstein AE, Nagy LE. Caspase-1 as a central regulator of high fat diet-induced non-alcoholic steatohepatitis. PLoS One 2013, 8(2): e56100.

28. Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol 2010, 11(2): 136-140.

29. Poitou C, Dalmas E, Renovato M, Benhamo V, Hajduch F, Abdennour M, et al. CD14dimCD16+ and CD14+CD16+ monocytes in obesity and during weight loss: relationships with fat mass and subclinical atherosclerosis. Arterioscler Thromb Vasc Biol 2011, 31(10): 2322-2330.

30. Wentworth JM, Naselli G, Brown WA, Doyle L, Phipson B, Smyth GK, et al. Pro-inflammatory CD11c+CD206+ adipose tissue macrophages are associated with insulin resistance in human obesity. Diabetes 2010, 59(7): 1648-1656.

31. Cohen HB, Mosser DM. Extrinsic and intrinsic control of macrophage inflammatory responses. J Leukoc Biol 2013, 94(5): 913-919.

32. Patsouris D, Li PP, Thapar D, Chapman J, Olefsky JM, Neels JG. Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab 2008, 8(4): 301-309.

33. Liu J, Divoux A, Sun J, Zhang J, Clement K, Glickman JN, et al. Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med 2009, 15(8): 940-945.

34. Herishanu Y, Rogowski O, Polliack A, Marilus R. Leukocytosis in obese individuals: possible link in patients with unexplained persistent neutrophilia. Eur J Haematol 2006, 76(6): 516-520.

35. Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 2009, 15(8): 930-939.

36. Stanley TL, Zanni MV, Johnsen S, Rasheed S, Makimura H, Lee H, et al. TNF-alpha antagonism with etanercept decreases glucose and increases the proportion of high molecular weight adiponectin in obese subjects with features of the metabolic syndrome. J Clin Endocrinol Metab 2011, 96(1): E146-150.

37. Liu M, Montgomery MK, Fiveash CE, Osborne B, Cooney GJ, Bell-Anderson K, et al. PPARalpha-independent actions of omega-3 PUFAs contribute to their beneficial effects on adiposity and glucose homeostasis. Sci Rep 2014, 4: 5538.

38. Karlsson EA, Beck MA. The burden of obesity on infectious disease. Exp Biol Med (Maywood) 2010, 235(12): 1412-1424.

39. Arslan E, Atilgan H, Yavasoglu I. The prevalence of Helicobacter pylori in obese subjects. Eur J Intern Med 2009, 20(7): 695-697.

40. Centers for Disease C, Prevention. Intensive-care patients with severe novel influenza A (H1N1) virus infection - Michigan, June 2009. MMWR Morb Mortal Wkly Rep 2009, 58(27): 749-752.

41. Jain S, Chaves SS. Obesity and influenza. Clin Infect Dis 2011, 53(5): 422-424.

42. Dossett LA, Dageforde LA, Swenson BR, Metzger R, Bonatti H, Sawyer RG, et al. Obesity and site-specific nosocomial infection risk in the intensive care unit. Surg Infect 2009, 10(2): 137-142.

43. Strandberg L, Verdrengh M, Enge M, Andersson N, Amu S, Onnheim K, et al. Mice chronically fed high-fat diet have increased mortality and disturbed immune response in sepsis. PloS one 2009, 4(10): e7605.

44. Smith AG, Sheridan PA, Harp JB, Beck MA. Diet-induced obese mice have increased mortality and altered immune responses when infected with influenza virus. J Nutr 2007, 137(5): 1236-1243.

45. Weber DJ, Rutala WA, Samsa GP, Santimaw JE, Lemon SM. Obesity as a predictor of poor antibody response to hepatitis B plasma vaccine. JAMA 1985, 254(22): 3187-3189.

46. Eliakim A, Schwindt C, Zaldivar F, Casali P, Cooper DM. Reduced tetanus antibody titers in overweight children. Autoimmunity 2006, 39(2): 137-141.

47. Callahan ST, Wolff M, Hill HR, Edwards KM, on behalf of the NV, Treatment Evaluation Unit Pandemic HNVSG. Impact of Body Mass Index on Immunogenicity of Pandemic H1N1 Vaccine in Children and Adults. J Infect Dis 2014.

48. Claycombe K, King LE, Fraker PJ. A role for leptin in sustaining lymphopoiesis and myelopoiesis. Proc Natl Acad Sci U S A 2008, 105(6): 2017-2021.

49. Nieman DC, Henson DA, Nehlsen-Cannarella SL, Ekkens M, Utter AC, Butterworth DE, et al. Influence of obesity on immune function. J Am Diet Assoc 1999, 99(3): 294-299.

50. Fontana L, Eagon JC, Colonna M, Klein S. Impaired mononuclear cell immune function in extreme obesity is corrected by weight loss. Rejuvenation Res 2007, 10(1): 41-46.

51. Vallerskog T, Martens GW, Kornfeld H. Diabetic mice display a delayed adaptive immune response to Mycobacterium tuberculosis. J Immunol 2010, 184(11): 6275-6282.

52. Lamas O, Marti A, Martinez JA. Obesity and immunocompetence. Eur J Clin Nutr 2002, 56 Suppl 3: S42-45.

53. Li Z, Soloski MJ, Diehl AM. Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease. Hepatology 2005, 42(4): 880-885.

54. Borges MC, Vinolo MA, Crisma AR, Fock RA, Borelli P, Tirapegui J, et al. High-fat diet blunts activation of the nuclear factor-kappaB signaling pathway in lipopolysaccharide-stimulated peritoneal macrophages of Wistar rats. Nutrition, 2013 29, 443-449..

55. Chinen J, Shearer WT. 6. Secondary immunodeficiencies, including HIV infection. J Allergy Clin Immunol 2008, 121(2 Suppl): S388-392; quiz S417.

56. Dooley KE, Chaisson RE. Tuberculosis and diabetes mellitus: convergence of two epidemics. Lancet Infect Dis 2009, 9(12): 737-746.

57. Chang JT, Dou HY, Yen CL, Wu YH, Huang RM, Lin HJ, et al. Effect of type 2 diabetes mellitus on the clinical severity and treatment outcome in patients with pulmonary tuberculosis: a potential role in the emergence of multidrug-resistance. J Formos Med Assoc 2011, 110(6): 372-381.

58. Chao WC, Yen CL, Wu YH, Chen SY, Hsieh CY, Chang TC, et al. Increased resistin may suppress reactive oxygen species production and inflammasome activation in type 2 diabetic patients with pulmonary tuberculosis infection. 2014 (in submission).

59. Wen Y, Gu J, Li SL, Reddy MA, Natarajan R, Nadler JL. Elevated glucose and diabetes promote interleukin-12 cytokine gene expression in mouse macrophages. Endocrinology 2006, 147(5): 2518-2525.

60. Shanmugam N, Reddy MA, Guha M, Natarajan R. High glucose-induced expression of proinflammatory cytokine and chemokine genes in monocytic cells. Diabetes 2003, 52(5): 1256-1264.

61. Sherry CL, O'Connor JC, Kramer JM, Freund GG. Augmented lipopolysaccharide-induced TNF-alpha production by peritoneal macrophages in type 2 diabetic mice is dependent on elevated glucose and requires p38 MAPK. J Immunol 2007, 178(2): 663-670.

62. Dasu MR, Devaraj S, Jialal I. High glucose induces IL-1beta expression in human monocytes: mechanistic insights. Am J Physiol Endocrinol Metab 2007, 293(1): E337-346.

63. Hill JR, Kwon G, Marshall CA, McDaniel ML. Hyperglycemic levels of glucose inhibit interleukin 1 release from RAW 264.7 murine macrophages by activation of protein kinase C. J Biol Chem 1998, 273(6): 3308-3313.

64. Sun C, Sun L, Ma H, Peng J, Zhen Y, Duan K, et al. The phenotype and functional alterations of macrophages in mice with hyperglycemia for long term. J Cell Physiol 2012, 227(4): 1670-1679.

65. Kushner RF. Weight loss strategies for treatment of obesity. Prog Cardiovasc Dis 2014, 56(4): 465-472.

66. Miras AD, le Roux CW. Mechanisms underlying weight loss after bariatric surgery. Nat Rev Gastroenterol Hepatol 2013, 10(10): 575-584.

67. Forsythe LK, Wallace JM, Livingstone MB. Obesity and inflammation: the effects of weight loss. Nutr Res Rev 2008, 21(2): 117-133.

68. Wing EJ, Stanko RT, Winkelstein A, Adibi SA. Fasting-enhanced immune effector mechanisms in obese subjects. Am J Med 1983, 75(1): 91-96.

69. Compher C, Badellino KO. Obesity and inflammation: lessons from bariatric surgery. JPEN J Parenter Enteral Nutr 2008, 32(6): 645-647.

70. Viardot A, Lord RV, Samaras K. The effects of weight loss and gastric banding on the innate and adaptive immune system in type 2 diabetes and prediabetes. J Clin Endocrinol Metab 2010, 95(6): 2845-2850.

71. Chang ZL. Important aspects of Toll-like receptors, ligands and their signaling pathways. Inflamm Res 2010, 59(10): 791-808.

72. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006, 124(4): 783-801.

73. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010, 11(5): 373-384.

74. Mogensen TH. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev 2009, 22(2): 240-273.

75. Tsan MF, Gao B. Endogenous ligands of Toll-like receptors. J Leukoc Biol 2004, 76(3): 514-519.

76. Drexler SK, Foxwell BM. The role of toll-like receptors in chronic inflammation. Int J Biochem Cell Biol 2010, 42(4): 506-518.

77. Kawai T, Akira S. TLR signaling. Semin Immunol 2007, 19(1): 24-32.

78. Hinz M, Arslan SC, Scheidereit C. It takes two to tango: IkappaBs, the multifunctional partners of NF-kappaB. Immunol Rev 2012, 246(1): 59-76.

79. Tse HM, Milton MJ, Schreiner S, Profozich JL, Trucco M, Piganelli JD. Disruption of innate-mediated proinflammatory cytokine and reactive oxygen species third signal leads to antigen-specific hyporesponsiveness. J Immunol 2007, 178(2): 908-917.

80. Hussain R, Kaleem A, Shahid F, Dojki M, Jamil B, Mehmood H, et al. Cytokine profiles using whole-blood assays can discriminate between tuberculosis patients and healthy endemic controls in a BCG-vaccinated population. J Immunol Methods 2002, 264(1-2): 95-108.

81. Segal AW. How neutrophils kill microbes. Annu Rev Immunol 2005, 23: 197-223.

82. El-Benna J, Dang PM, Gougerot-Pocidalo MA. Priming of the neutrophil NADPH oxidase activation: role of p47phox phosphorylation and NOX2 mobilization to the plasma membrane. Semin Immunopathol 2008, 30(3): 279-289.

83. Miklos G, Andra K, Erzse L, Chronic granulomatous disease: more than the lack of superoxide? J Leukoc Biol 2001, 14: 8010-8014.

84. Yan Z, Banerjee R. Redox remodeling as an immunoregulatory strategy. Biochemistry 2010, 49(6): 1059-1066.

85. Liu SY, Tsai MY, Chuang KP, Huang YF, Shieh CC. Ligand binding of leukocyte integrin very late antigen-4 involves exposure of sulfhydryl groups and is subject to redox modulation. Eur J Immunol 2008, 38(2): 410-423.

86. Liu SY, Wang WZ, Yen CL, Tsai MY, Yang PW, Wang JY, et al. Leukocyte nicotinamide adenine dinucleotide phosphate-reduced oxidase is required for isocyanate-induced lung inflammation. J Allergy Clin Immunol 2011, 127(4): 1014-1023.

87. Woodgett JR. Judging a protein by more than its name: GSK-3. Sci STKE 2001, 2001(100): re12.

88. Fang X, Yu S, Tanyi JL, Lu Y, Woodgett JR, Mills GB. Convergence of multiple signaling cascades at glycogen synthase kinase 3: Edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase C-dependent intracellular pathway. Mol Cell Biol 2002, 22(7): 2099-2110.

89. Quan J, Liu J, Gao X, Liu J, Yang H, Chen W, et al. Palmitate induces interleukin-8 expression in human aortic vascular smooth muscle cells via Toll-like receptor 4/nuclear factor-kappaB pathway. J Diabetes 2014, 6(1): 33-41.

90. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995, 378(6559): 785-789.

91. van den BG, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001, 345(19): 1359-1367.

92. Kenzel S, Mergen M, von Susskind-Schwendi J, Wennekamp J, Deshmukh SD, Haeffner M, et al. Insulin modulates the inflammatory granulocyte response to streptococci via phosphatidylinositol 3-kinase. J Immunol 2012, 189(9): 4582-4591.

93. Steinbrecher KA, Wilson W, 3rd, Cogswell PC, Baldwin AS. Glycogen synthase kinase 3beta functions to specify gene-specific, NF-kappaB-dependent transcription. Mol Cell Biol 2005, 25(19): 8444-8455.

94. Martin M, Rehani K, Jope RS, Michalek SM. Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat Immunol 2005, 6(8): 777-784.

95. Saraiva M, O'Garra A. The regulation of IL-10 production by immune cells. Nat Rev Immunol 2010, 10(3): 170-181.

96. Wen AY, Sakamoto KM, Miller LS. The role of the transcription factor CREB in immune function. J Immunol 2010, 185(11): 6413-6419.

97. Chan MM, Cheung BK, Li JC, Chan LL, Lau AS. A role for glycogen synthase kinase-3 in antagonizing mycobacterial immune evasion by negatively regulating IL-10 induction. J Leukoc Biol 2009, 86(2): 283-291.

98. Medina EA, Morris IR, Berton MT. Phosphatidylinositol 3-kinase activation attenuates the TLR2-mediated macrophage proinflammatory cytokine response to Francisella tularensis live vaccine strain. J Immunol 2010, 185(12): 7562-7572.

99. Nandan D, Camargo de Oliveira C, Moeenrezakhanlou A, Lopez M, Silverman JM, Subek J, et al. Myeloid cell IL-10 production in response to leishmania involves inactivation of glycogen synthase kinase-3beta downstream of phosphatidylinositol-3 kinase. J Immunol 2012, 188(1): 367-378.

100. Hsu MC, Chang CS, Lee KT, Sun HY, Tsai YS, Kuo PH, et al. Central obesity in males affected by a dyslipidemia-associated genetic polymorphism on APOA1/C3/A4/A5 gene cluster. Nutri Diabetes 2013, 3: e61.

101. Feinberg J, Fieschi C, Doffinger R, Feinberg M, Leclerc T, Boisson-Dupuis S, et al. Bacillus Calmette Guerin triggers the IL-12/IFN-gamma axis by an IRAK-4- and NEMO-dependent, non-cognate interaction between monocytes, NK, and T lymphocytes. Euro J Immunol 2004, 34(11): 3276-3284.

102. Huang WC, Tsai CC, Chen CL, Chen TY, Chen YP, Lin YS, et al. Glucosylceramide synthase inhibitor PDMP sensitizes chronic myeloid leukemia T315I mutant to Bcr-Abl inhibitor and cooperatively induces glycogen synthase kinase-3-regulated apoptosis. FASEB J 2011, 25(10): 3661-3673.

103. van Dooren FH, Duijvis NW, te Velde AA. Analysis of cytokines and chemokines produced by whole blood, peripheral mononuclear and polymorphonuclear cells. J Immunol Methods 2013, 396(1-2): 128-133.

104. Xing L, Remick DG. Relative cytokine and cytokine inhibitor production by mononuclear cells and neutrophils. Shock 2003, 20(1): 10-16.

105. Damsgaard CT, Lauritzen L, Calder PC, Kjaer TM, Frokiaer H. Whole-blood culture is a valid low-cost method to measure monocytic cytokines - a comparison of cytokine production in cultures of human whole-blood, mononuclear cells and monocytes. J Immunol Methods 2009, 340(2): 95-101.

106. Staehr P, Hother-Nielsen O, Landau BR, Chandramouli V, Holst JJ, Beck-Nielsen H. Effects of free fatty acids per se on glucose production, gluconeogenesis, and glycogenolysis. Diabetes 2003, 52(2): 260-267.

107. Yen CL, Chao WC, Wu CH, Huang YF, Chang CS, Tsai YS, et al. Phosphorylation of glycogen synthase kinase-3beta in metabolically abnormal obesity affects immune stimulation-induced cytokine production. Int J Obes (Lond) 2014.

108. Andersson CX, Gustafson B, Hammarstedt A, Hedjazifar S, Smith U. Inflamed adipose tissue, insulin resistance and vascular injury. Diabetes Metab Res Rev 2008, 24(8): 595-603.

109. Falagas ME, Kompoti M. Obesity and infection. The Lancet infectious diseases 2006, 6(7): 438-446.

110. Gleeson M, Bishop N, Oliveira M, McCauley T, Tauler P, Muhamad AS. Respiratory infection risk in athletes: association with antigen-stimulated IL-10 production and salivary IgA secretion. Scand J Med Sci Sports 2012, 22(3): 410-417.

111. Turina M, Fry DE, Polk HC, Jr. Acute hyperglycemia and the innate immune system: clinical, cellular, and molecular aspects. Crit Care Med 2005, 33(7): 1624-1633.

112. Kidd LB, Schabbauer GA, Luyendyk JP, Holscher TD, Tilley RE, Tencati M, et al. Insulin activation of the phosphatidylinositol 3-kinase/protein kinase B (Akt) pathway reduces lipopolysaccharide-induced inflammation in mice. J Pharmacol Exp Ther 2008, 326(1): 348-353.

113. Cohen P. The Croonian Lecture 1998. Identification of a protein kinase cascade of major importance in insulin signal transduction. Philos Trans R Soc Lond B Biol Sci 1999, 354(1382): 485-495.

114. van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive insulin therapy in critically ill patients. N Eng J Med 2001, 345(19): 1359-1367.

115. Zhou Q, Leeman SE, Amar S. Signaling mechanisms involved in altered function of macrophages from diet-induced obese mice affect immune responses. Proc Natl Acad Sci U S A 2009, 106(26): 10740-10745.

116. Cremer TJ, Shah P, Cormet-Boyaka E, Valvano MA, Butchar JP, Tridandapani S. Akt-mediated proinflammatory response of mononuclear phagocytes infected with Burkholderia cenocepacia occurs by a novel GSK3beta-dependent, IkappaB kinase-independent mechanism. J Immunol 2011, 187(2): 635-643.

117. Hansen T, Rehfeld JF, Nielsen FC. GSK-3beta reduces cAMP-induced cholecystokinin gene expression by inhibiting CREB binding. Neuroreport 2004, 15(5): 841-845.

118. Park SH, Park-Min KH, Chen J, Hu X, Ivashkiv LB. Tumor necrosis factor induces GSK3 kinase-mediated cross-tolerance to endotoxin in macrophages. Nat Immunol 2011, 12(7): 607-615.

119. Maury E, Brichard SM. Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Mol Cell Endocrinol 2010, 314(1): 1-16.

120. Cohen G, Ilic D, Raupachova J, Horl WH. Resistin inhibits essential functions of polymorphonuclear leukocytes. J Immunol 2008, 181(6): 3761-3768.

121. Querec T, Bennouna S, Alkan S, Laouar Y, Gorden K, Flavell R, et al. Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity. J Exp Med 2006, 203(2): 413-424.

122. Napolitani G, Rinaldi A, Bertoni F, Sallusto F, Lanzavecchia A. Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells. Nat Immunol 2005, 6(8): 769-776.

123. Park HL, Shim SH, Lee EY, Cho W, Park S, Jeon HJ, et al. Obesity-induced chronic inflammation is associated with the reduced efficacy of influenza vaccine. Hum Vaccin Immunother 2014, 10(5).

124. Mathews CE, Brown EL, Martinez PJ, Bagaria U, Nahm MH, Burton RL, et al. Impaired function of antibodies to pneumococcal surface protein A but not to capsular polysaccharide in Mexican American adults with type 2 diabetes mellitus. Clin Vaccine Immunol 2012, 19(9): 1360-1369.

125. Lefebvre JS, Haynes L. Vaccine strategies to enhance immune responses in the aged. Curr Opin Immunol 2013, 25(4): 523-528.

126. Ban JO, Kwak DH, Oh JH, Park EJ, Cho MC, Song HS, et al. Suppression of NF-kappaB and GSK-3beta is involved in colon cancer cell growth inhibition by the PPAR agonist troglitazone. Chem Biol Interact 2010, 188(1): 75-85.

127. Lee S, Yang WK, Song JH, Ra YM, Jeong JH, Choe W, et al. Anti-obesity effects of 3-hydroxychromone derivative, a novel small-molecule inhibitor of glycogen synthase kinase-3. Biochem Pharmacol 2013, 85(7): 965-976.
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