İnflamazomların Karaciğer Toksisitesindeki Rolü

Year 2019, Volume: 39 Issue: 2, 90 - 97, 01.06.2019

Fatma İspir Şaziye Sezin Yücelik

Abstract

İnflamazomlar, enfeksiyona neden olan mikroorganizmalara ve konak proteinlerinden oluşan moleküllere karşı inflamasyonun başlatılmasından sorumlu olan multiprotein komplekslerdir. Reseptör, adaptör ve efektör proteinlerin bir araya gelmesi sonucu oluşan inflamazomların pirin içeren NOD benzeri reseptör 1 (NLRP1), NLRP2, NLRP3, NLRP6, NLRP10, NLRP12, NLRC4 ve AIM2 olmak üzere 8 farklı tipi tanımlanmıştır. NLRP3 inflamazomu, neredeyse her türlü tehlike sinyalini tanıma özelliğine sahip olmasıyla öne çıkan ve günümüze kadar en fazla araştırılan inflamazomdur. Patojen ilişkili moleküler kalıplar (pathogen-associated moleculer pattern; PAMP) ve hasarlı veya ölen hücrelerin endojen sinyalleri (damage/danger-associated molecular pattern; DAMP) ile aktive olan NLRP3 inflamazomu kaspaz-1 aktive ederek IL-1β ve IL-18 sitokinlerinin salınmasına yol açmaktadır. Karaciğer ilk geçiş organı olmasından ötürü çeşitli mikrobiyal partiküllerle mücadale halindedir. Bu sırada çok sayıda sitozolik patojen, inflamazomlar tarafından algılanabilir. İnflamazomlar, hepatositler, karaciğer sinüzoidal endotel hücreleri, hepatik stellat hücreleri ve makrofajlarda aktif olarak ifade edilir. Patojenlere ve tehlike sinyallerine karşı karaciğer savunması için esas olan inflamazomların aşırı aktivasyonu ise çeşitli karaciğer hastalıklarının patojenezini artırır. Bu derleme kapsamında inflamazomların yapıları, çeşitleri, aktivasyonları ve karaciğer toksisitesinde ki rolleri incelenmiştir.

Keywords

inflamazom, hepatotoksisite

References

• 1. Wang J, Dong R, Zheng S: Roles of the inflammasome in the gutliver axis (Review). Molecular Medicine Reports 2019, 19(1): 3-14.
• 2. Sharma D, Kanneganti TD: The cell biology of inflammasomes: Mechanisms of inflammasome activation and regulation. Journal of Cell Biology 2016, 213(6): 617-29.
• 3. Szabo G, Csak T: Inflammasomes in liver diseases. Journal of Hepatology 2012, 57(3): 642-54.
• 4. Kigerl KA, de Rivero Vaccari JP, Dietrich WD, Popovich PG, Keane RW: Pattern recognition receptors and central nervous system repair. Experimental Neurology 2014, 2585-16.
• 5. Amin J, Boche D, Rakic S: What do we know about the inflammasome in humans? Brain Pathology 2017, 27(2): 192-204.
• 6. Kim YK, Shin JS, Nahm MH: NOD-Like Receptors in Infection, Immunity, and Diseases. Yonsei Medical Journal 2016, 57(1): 5-14.
• 7. Di Virgilio F: The therapeutic potential of modifying inflammasomes and NOD-like receptors. Pharmacological Reviews 2013, 65(3): 872-905.
• 8. Luan J, Ju D: Inflammasome: A Double-Edged Sword in Liver Diseases. Frontiers in Immunology 2018, 92201.
• 9. Xiao J, Tipoe GL: Inflammasomes in non-alcoholic fatty liver disease. Frontiers in Bioscience (Landmark Ed) 2016, 21683-95.
• 10. Ratsimandresy RA, Dorfleutner A, Stehlik C: An Update on PYRIN Domain-Containing Pattern Recognition Receptors: From Immunity to Pathology. Frontiers in Immunology 2013, 4440.
• 11. Khare S, Luc N, Dorfleutner A, Stehlik C: Inflammasomes and their activation. Critical Reviews in Immunology 2010, 30(5): 463-87.
• 12. Schroder K, Tschopp J: The inflammasomes. Cell 2010, 140(6): 821-32.
• 13. de Rivero Vaccari JP, Dietrich WD, Keane RW: Activation and regulation of cellular inflammasomes: gaps in our knowledge for central nervous system injury. Journal of Cerebral Blood Flow & Metabolism 2014, 34(3): 369-75.
• 14. Davis BK, Wen H, Ting JP: The inflammasome NLRs in immunity, inflammation, and associated diseases. Annual Review of Immunology 2011, 29707-35.
• 15. Beger RD, Bhattacharyya S, Yang X, Gill PS, Schnackenberg LK, Sun J, James LP: Translational biomarkers of acetaminophen-induced acute liver injury. Archives of Toxicology 2015, 89(9): 1497-522.
• 16. James LP, Farrar HC, Darville TL, Sullivan JE, Givens TG, Kearns GL, Wasserman GS, Simpson PM, Hinson JA: Elevation of serum interleukin 8 levels in acetaminophen overdose in children and adolescents. Clinical Pharmacology & Therapeutics 2001, 70(3): 280-6.
• 17. Blazka ME, Wilmer JL, Holladay SD, Wilson RE, Luster MI: Role of proinflammatory cytokines in acetaminophen hepatotoxicity. Toxicology and Applied Pharmacology 1995, 133(1): 43-52.
• 18. Imaeda AB, Watanabe A, Sohail MA, Mahmood S, Mohamadnejad M, Sutterwala FS, Flavell RA, Mehal WZ: Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome. Journal of Clinical Investigation 2009, 119(2): 305-14.
• 19. Ishibe T, Kimura A, Ishida Y, Takayasu T, Hayashi T, Tsuneyama K, Matsushima K, Sakata I, Mukaida N, Kondo T: Reduced acetaminophen-induced liver injury in mice by genetic disruption of IL-1 receptor antagonist. Laboratory Investigation 2009, 89(1): 68-79.
• 20. Chen CJ, Kono H, Golenbock D, Reed G, Akira S, Rock KL: Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nature Medicine 2007, 13(7): 851-6.
• 21. Williams CD, Antoine DJ, Shaw PJ, Benson C, Farhood A, Williams DP, Kanneganti TD, Park BK, Jaeschke H: Role of the Nalp3 inflammasome in acetaminophen-induced sterile inflammation and liver injury. Toxicology and Applied Pharmacology 2011, 252(3): 289-97.
• 22. Hu J, Yan D, Gao J, Xu C, Yuan Y, Zhu R, Xiang D, Weng S, Han W, Zang G, Yu Y: rhIL-1Ra reduces hepatocellular apoptosis in mice with acetaminophen-induced acute liver failure. Laboratory Investigation 2010, 90(12): 1737-46.
• 23. Wu X, Dong L, Lin X, Li J: Relevance of the NLRP3 Inflammasome in the Pathogenesis of Chronic Liver Disease. Frontiers in Immunology 2017, 81728.
• 24. Colletti LM, Remick DG, Burtch GD, Kunkel SL, Strieter RM, Campbell DA, Jr.: Role of tumor necrosis factor-alpha in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat. Journal of Clinical Investigation 1990, 85(6): 1936-43.
• 25. Shito M, Wakabayashi G, Ueda M, Shimazu M, Shirasugi N, Endo M, Mukai M, Kitajima M: Interleukin 1 receptor blockade reduces tumor necrosis factor production, tissue injury, and mortality after hepatic ischemia-reperfusion in the rat. Transplantation 1997, 63(1): 143-8.
• 26. Zhu P, Duan L, Chen J, Xiong A, Xu Q, Zhang H, Zheng F, Tan Z, Gong F, Fang M: Gene silencing of NALP3 protects against liver ischemia-reperfusion injury in mice. Human Gene Therapy 2011, 22(7): 853-64.
• 27. Shimizu S, Eguchi Y, Kamiike W, Akao Y, Kosaka H, Hasegawa J, Matsuda H, Tsujimoto Y: Involvement of ICE family proteases in apoptosis induced by reoxygenation of hypoxic hepatocytes. American Journal of Physiology 1996, 271(6 Pt 1): G949-58.
• 28. Menzel CL, Sun Q, Loughran PA, Pape HC, Billiar TR, Scott MJ: Caspase-1 is hepatoprotective during trauma and hemorrhagic shock by reducing liver injury and inflammation. Molecular Medicine 2011, 17(9-10): 1031-8.
• 29. Valles SL, Blanco AM, Azorin I, Guasch R, Pascual M, Gomez-Lechon MJ, Renau-Piqueras J, Guerri C: Chronic ethanol consumption enhances interleukin-1-mediated signal transduction in rat liver and in cultured hepatocytes. Alcoholism: Clinical and Experimental Research 2003, 27(12): 1979-86.
• 30. McClain CJ, Cohen DA, Dinarello CA, Cannon JG, Shedlofsky SI, Kaplan AM: Serum interleukin-1 (IL-1) activity in alcoholic hepatitis. Life Sciences 1986, 39(16): 1479-85.
• 31. Nagy LE: The Role of Innate Immunity in Alcoholic Liver Disease. Alcohol Research: Current Reviews 2015, 37(2): 237-50.
• 32. Hsiang CY, Wu SL, Cheng SE, Ho TY: Acetaldehyde-induced interleukin-1beta and tumor necrosis factor-alpha production is inhibited by berberine through nuclear factor-kappaB signaling pathway in HepG2 cells. Journal of Biomedical Science 2005, 12(5): 791-801.
• 33. Szabo G, Petrasek J: Inflammasome activation and function in liver disease. Nature Reviews Gastroenterology & Hepatology 2015, 12(7): 387-400.
• 34. Petrasek J, Bala S, Csak T, Lippai D, Kodys K, Menashy V, Barrieau M, Min SY, Kurt-Jones EA, Szabo G: IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. Journal of Clinical Investigation 2012, 122(10): 3476-89.
• 35. Voican CS, Njike-Nakseu M, Boujedidi H, Barri-Ova N, Bouchet-Delbos L, Agostini H, Maitre S, Prevot S, Cassard-Doulcier AM, Naveau S, Perlemuter G: Alcohol withdrawal alleviates adipose tissue inflammation in patients with alcoholic liver disease. Liver International 2015, 35(3): 967-78.
• 36. DeSantis DA, Ko CW, Liu Y, Liu X, Hise AG, Nunez G, Croniger CM: Alcohol-induced liver injury is modulated by Nlrp3 and Nlrc4 inflammasomes in mice. Mediators of Inflammation 2013, 2013751374.
• 37. Molyvdas A, Georgopoulou U, Lazaridis N, Hytiroglou P, Dimitriadis A, Foka P, Vassiliadis T, Loli G, Phillipidis A, Zebekakis P, Germenis AE, Speletas M, Germanidis G: The role of the NLRP3 inflammasome and the activation of IL-1beta in the pathogenesis of chronic viral hepatic inflammation. Cytokine 2018, 110389-396.
• 38. Negash AA, Ramos HJ, Crochet N, Lau DT, Doehle B, Papic N, Delker DA, Jo J, Bertoletti A, Hagedorn CH, Gale M, Jr.: IL-1beta production through the NLRP3 inflammasome by hepatic macrophages links hepatitis C virus infection with liver inflammation and disease. PLoS Pathogens 2013, 9(4): e1003330.