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Cân bằng thay đổi giữa interleukin-13/interferon-gamma góp phần vào sự tàn phá của tuyến lệ và rối loạn secretory trong mô hình CD25 knockout của hội chứng Sjögren
Tóm tắt
Tuyến lệ (LG) trong mô hình CD25-/- của hội chứng Sjögren (SS) có nồng độ cao các cytokine interleukin (IL)-17, IL-13 và interferon-gamma (IFN-γ). Đóng góp cụ thể của những cytokine này vào sự khởi phát và mức độ nghiêm trọng của bệnh viêm tuyến lệ ở chuột CD25-/- chưa được đánh giá. Các dòng chuột CD25−/−IL-17A−/−, CD25−/−IL-17−/−IFN-γ−/− và CD25−/−IFN-γ−/− được sử dụng ở 4, 8, 12, 16 tuần (W). Sự xâm nhập của tế bào lympho tổng thể được đánh giá bằng hình thái học và được phân loại bằng phân tích dòng tế bào. Nồng độ yếu tố tăng trưởng biểu bì (EGF) được đo trong nước mắt. Kỹ thuật nhuộm miễn dịch huỳnh quang đánh giá sự biểu hiện của thụ thể IFN-γ (IFN-γR) và quá trình apoptosis. PCR thời gian thực được sử dụng để đánh giá sự biểu hiện của cytokine liên quan đến viêm và tế bào T trong LG. Hoạt tính caspase-3, -8, -9 được kiểm tra trong dịch chiết từ LG. Các cytokine tế bào T helper được đo trong huyết thanh bằng phương pháp Luminex. Sự xâm nhập tổng thể của LG ở 8 W lớn nhất được ghi nhận ở CD25−/−IL-17A−/− (95%), tiếp theo là CD25−/− (71%) và IL-17−/− (12%). Nồng độ EGF trong nước mắt ở CD25−/− nằm trong khoảng bình thường ở 4 W và ở mức rất thấp ở cả CD25−/− và CD25−/−IL-17A−/−. CD25−/− có nồng độ cao các bản sao của cytokine viêm trong LG so với chuột IL-17−/−; tuy nhiên, CD25−/−IL-17A−/− có nồng độ mRNA IL-1β, IFN-γR, caspase-3, -8, -9 cao hơn, có tính phản ứng miễn dịch lớn hơn với IFN-γR trong acini LG, số lượng tế bào apoptotic+ lớn hơn và hoạt tính caspases cao hơn trong LG ở 8 W. CD25−/−IL-17A−/− có nồng độ IL-13 thấp hơn và tỷ lệ IL-13/IFN-γ thấp hơn so với CD25−/− trong huyết thanh. CD25−/−IFN-γ−/− có số lượng tế bào apoptotic+ thấp hơn và giảm biểu hiện caspase-3 trong LG. CD25−/−IL-17−/−IFN-γ−/− có xâm nhập tế bào lympho tổng thể thấp hơn ở 8 W (48%), xâm nhập tế bào T CD4+ và biểu hiện của IFN-γR và tế bào apoptotic+ trong LG, cùng với tăng nồng độ EGF trong nước mắt. IFN-γ là yếu tố chính trong sự tàn phá và rối loạn chức năng bài tiết của LG trong mô hình CD25−/− của SS. Cân bằng thay đổi giữa IFN-γ và IL-13 trong chuột CD25−/−IL-17A−/− làm tăng tốc quá trình tàn phá LG bằng cách tăng apoptosis ở tuyến và tạo điều kiện cho apoptosis thông qua việc tăng cường biểu hiện IFN-γR của biểu mô tuyến và kích hoạt caspases. Việc nhắm mục tiêu cả IFN-γ và IL-17 có thể mang lại lợi ích trong điều trị viêm LG trong SS.
Từ khóa
#tuyến lệ #hội chứng Sjögren #cytokine #interleukin-17 #interferon-gamma #chống viêm #tế bào lympho #apoptosisTài liệu tham khảo
Stern ME, Gao J, Schwalb TA, Ngo M, Tieu DD, Chan CC, et al. Conjunctival T-cell subpopulations in Sjogren’s and non-Sjogren’s patients with dry eye. Invest Ophthalmol Vis Sci. 2002;43:2609–14.
Zoukhri D, Hodges RR, Byon D, Kublin CL. Role of proinflammatory cytokines in the impaired lacrimation associated with autoimmune xerophthalmia. Invest Ophthalmol Vis Sci. 2002;43:1429–36.
Naito Y, Matsumoto I, Wakamatsu E, Goto D, Sugiyama T, Matsumura R, et al. Muscarinic acetylcholine receptor autoantibodies in patients with Sjogren’s syndrome. Ann Rheum Dis. 2005;64:510–1.
Bacman S, Sterin-Borda L, Camusso JJ, Arana R, Hubscher O, Borda E. Circulating antibodies against rat parotid gland M3 muscarinic receptors in primary Sjogren’s syndrome. Clin Exp Immunol. 1996;104:454–9.
Bacman S, Perez LC, Sterin-Borda L, Hubscher O, Arana R, Borda E. Autoantibodies against lacrimal gland M3 muscarinic acetylcholine receptors in patients with primary Sjogren’s syndrome. Invest Ophthalmol Vis Sci. 1998;39:151–6.
Sharma R, Zheng L, Guo X, Fu SM, Ju ST, Jarjour WN. Novel animal models for Sjogren’s syndrome: expression and transfer of salivary gland dysfunction from regulatory T cell-deficient mice. J Autoimmun. 2006;27:289–96.
Rahimy E, Pitcher III JD, Pangelinan SB, Chen W, Farley WJ, Niederkorn JY, et al. Spontaneous autoimmune dacryoadenitis in aged CD25KO mice. Am J Pathol. 2010;177:744–53.
Sadlack B, Lohler J, Schorle H, Klebb G, Haber H, Sickel E, et al. Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells. Eur J Immunol. 1995;25:3053–9.
Sadlack B, Merz H, Schorle H, Schimpl A, Feller AC, Horak I. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell. 1993;75:253–61.
Sharma R, Bagavant H, Jarjour WN, Sung SS, Ju ST. The role of Fas in the immune system biology of IL-2R alpha knockout mice: interplay among regulatory T cells, inflammation, hemopoiesis, and apoptosis. J Immunol. 2005;175:1965–73.
de Paiva CS, Hwang CS, Pitcher III JD, Pangelinan SB, Rahimy E, Chen W, et al. Age-related T-cell cytokine profile parallels corneal disease severity in Sjogren’s syndrome-like keratoconjunctivitis sicca in CD25KO mice. Rheumatology (Oxford). 2010;49:246–58.
Lan RY, Salunga TL, Tsuneyama K, Lian ZX, Yang GX, Hsu W, et al. Hepatic IL-17 responses in human and murine primary biliary cirrhosis. J Autoimmun. 2009;32:43–51.
Cha S, Brayer J, Gao J, Brown V, Killedar S, Yasunari U, et al. A dual role for interferon-gamma in the pathogenesis of Sjogren’s syndrome-like autoimmune exocrinopathy in the nonobese diabetic mouse. Scand J Immunol. 2004;60:552–65.
Pelegrino FS, Volpe EA, Gandhi NB, Li DQ, Pflugfelder SC, de Paiva CS. Deletion of interferon-gamma delays onset and severity of dacryoadenitis in CD25KO mice. Arthritis Res Ther. 2012;14:R234.
Ford JG, Rennick D, Donaldson DD, Venkayya R, McArthur C, Hansell E, et al. Il-13 and IFN-gamma: interactions in lung inflammation. J Immunol. 2001;167:1769–77.
Shahzeidi S, Aujla PK, Nickola TJ, Chen Y, Alimam MZ, Rose MC. Temporal analysis of goblet cells and mucin gene expression in murine models of allergic asthma. Exp Lung Res. 2003;29:549–65.
Tran MT, Tellaetxe-Isusi M, Elner V, Strieter RM, Laush RN, Oaks JE. Proinflammatory cytokines induce RANTES and MCP-1 synthesis in human corneal keratocytes but not in corneal epithelial cells. B-chemokine synthesis in corneal cells. Invest Ophthalmol Vis Sci. 1996;37:987–96.
Kondo M, Tamaoki J, Takeyama K, Isono K, Kawatani K, Izumo T, et al. Elimination of IL-13 reverses established goblet cell metaplasia into ciliated epithelia in airway epithelial cell culture. Allergol Int. 2006;55:329–36.
Singhera GK, Macredmond R, Dorscheid DR. Interleukin-9 and -13 inhibit spontaneous and corticosteroid induced apoptosis of normal airway epithelial cells. Exp Lung Res. 2008;34:579–98.
Wright K, Kolios G, Westwick J, Ward SG. Cytokine-induced apoptosis in epithelial HT-29 cells is independent of nitric oxide formation. Evidence for an interleukin-13-driven phosphatidylinositol 3-kinase-dependent survival mechanism. J Biol Chem. 1999;274:17193–201.
Iwakura Y, Ishigame H. The IL-23/IL-17 axis in inflammation. J Clin Invest. 2006;116:1218–22.
de Paiva CS, Chotikavanich S, Pangelinan SB, Pitcher JI, Fang B, Zheng X, et al. IL-17 disrupts corneal barrier following desiccating stress. Mucosal Immunol. 2009;2:243–53.
Strong B, Farley W, Stern ME, Pflugfelder SC. Topical cyclosporine inhibits conjunctival epithelial apoptosis in experimental murine keratoconjunctivitis sicca. Cornea. 2005;24:80–5.
Fujitsu Y, Fukuda K, Kimura K, Seki K, Kumagai N, Nishida T. Protection of human conjunctival fibroblasts from NO-induced apoptosis by interleukin-4 or interleukin-13. Invest Ophthalmol Vis Sci. 2005;46:797–802.
Zhang X, Chen W, de Paiva CS, Corrales RM, Volpe EA, McClellan AJ, et al. Interferon-gamma exacerbates dry eye-induced apoptosis in conjunctiva through dual apoptotic pathways. Invest Ophthalmol Vis Sci. 2011;52:6279–85.
Xiao S, Sung SS, Fu SM, Ju ST. Combining Fas mutation with interleukin-2 deficiency prevents colitis and lupus: implicating interleukin-2 for auto-reactive T cell expansion and Fas ligand for colon epithelial cell death. J Biol Chem. 2003;278:52730–8.
D’Souza SD, Bonetti B, Balasingam V, Cashman NR, Barker PA, Troutt AB, et al. Multiple sclerosis: Fas signaling in oligodendrocyte cell death. J Exp Med. 1996;184:2361–70.
Stassi G, De MR, Trucco G, Rudert W, Testi R, Galluzzo A, et al. Nitric oxide primes pancreatic beta cells for Fas-mediated destruction in insulin-dependent diabetes mellitus. J Exp Med. 1997;186:1193–200.
Zhang X, Chen W, de Paiva CS, Volpe EA, Gandhi NB, Farley WJ, et al. Desiccating stress induces CD4(+) T-cell-mediated Sjogren’s syndrome-like corneal epithelial apoptosis via activation of the extrinsic apoptotic pathway by interferon-gamma. Am J Pathol. 2011;179:1807–14.
Zhang X, de Paiva CS, Su Z, Volpe EA, Li DQ, Pflugfelder SC. Topical interferon-gamma neutralization prevents conjunctival goblet cell loss in experimental murine dry eye. Exp Eye Res. 2014;118:117–24.
Zoukhri D, Macari E, Kublin CL. A single injection of interleukin-1 induces reversible aqueous-tear deficiency, lacrimal gland inflammation, and acinar and ductal cell proliferation. Exp Eye Res. 2007;84:894–904.
Zoukhri D, Ko S, Stark PC, Kublin CL. Roles of caspase 1 and extracellular signal-regulated kinase in inflammation-induced inhibition of lacrimal gland protein secretion. Invest Ophthalmol Vis Sci. 2008;49:4392–8.
Shirey KA, Jung JY, Maeder GS, Carlin JM. Upregulation of IFN-gamma receptor expression by proinflammatory cytokines influences IDO activation in epithelial cells. J Interferon Cytokine Res. 2006;26:53–62.
Schwarting A, Wada T, Kinoshita K, Tesch G, Kelley VR. IFN-gamma receptor signaling is essential for the initiation, acceleration, and destruction of autoimmune kidney disease in MRL-Fas(lpr) mice. J Immunol. 1998;161:494–503.
O’Connell J, Bennett MW, Nally K, O’Sullivan GC, Collins JK, Shanahan F. Interferon-gamma sensitizes colonic epithelial cell lines to physiological and therapeutic inducers of colonocyte apoptosis. J Cell Physiol. 2000;185:331–8.
Guo Z, Song D, Azzarolo AM, Schechter JE, Warren DW, Wood RL, et al. Autologous lacrimal-lymphoid mixed-cell reactions induce dacryoadenitis in rabbits. Exp Eye Res. 2000;71:23–31.
Nguyen CQ, Hu MH, Li Y, Stewart C, Peck AB. Salivary gland tissue expression of interleukin-23 and interleukin-17 in Sjogren’s syndrome: findings in humans and mice. Arthritis Rheum. 2008;58:734–43.
Katsifis GE, Rekka S, Moutsopoulos NM, Pillemer S, Wahl SM. Systemic and local interleukin-17 and linked cytokines associated with Sjogren’s syndrome immunopathogenesis. Am J Pathol. 2009;175:1167–77.
Chauhan SK, El AJ, Ecoiffier T, Goyal S, Zhang Q, Saban DR, et al. Autoimmunity in dry eye is due to resistance of Th17 to Treg suppression. J Immunol. 2009;182:1247–52.
Jie G, Jiang Q, Rui Z, Yifei Y. Expression of interleukin-17 in autoimmune dacryoadenitis in MRL/lpr mice. Curr Eye Res. 2010;35:865–71.
Nguyen CQ, Yin H, Lee BH, Carcamo WC, Chiorini JA, Peck AB. Pathogenic effect of interleukin-17A in induction of Sjogren’s syndrome-like disease using adenovirus-mediated gene transfer. Arthritis Res Ther. 2010;12:R220.
Nguyen CQ, Yin H, Lee BH, Chiorini JA, Peck AB. IL17: potential therapeutic target in Sjogren’s syndrome using adenovirus-mediated gene transfer. Lab Invest. 2011;91:54–62.
Lin X, Rui K, Deng J, Tian J, Wang X, Wang S, et al. Th17 cells play a critical role in the development of experimental Sjogren’s syndrome. Ann Rheum Dis 2014. doi:10.1136/annrheumdis-2013-204584.
Ogawa A, Andoh A, Araki Y, Bamba T, Fujiyama Y. Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice. Clin Immunol. 2004;110:55–62.
Yang W, Yao Y, Yang YQ, Lu FT, Li L, Wang YH, et al. Differential modulation by IL-17A of cholangitis versus colitis in IL-2Ralpha deleted mice. PLoS One. 2014;9:e105351.
Luger D, Silver PB, Tang J, Cua D, Chen Z, Iwakura Y, et al. Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category. J Exp Med. 2008;205:799–810.
Billiau A, Heremans H, Vandekerckhove F, Dijkmans R, Sobis H, Meulepas E, et al. Enhancement of experimental allergic encephalomyelitis in mice by antibodies against IFN-gamma. J Immunol. 1988;140:1506–10.
Caspi RR, Chan CC, Grubbs BG, Silver PB, Wiggert B, Parsa CF, et al. Endogenous systemic IFN-gamma has a protective role against ocular autoimmunity in mice. J Immunol. 1994;152:890–9.
Willerford DM, Chen J, Ferry JA, Davidson L, Ma A, Alt FW. Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity. 1995;3:521–30.
Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, et al. Targeted disruption of the mouse-transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature. 1992;359:693–9.
McCartney-Francis NL, Mizel DE, Frazier-Jessen M, Kulkarni AB, McCarthy JB, Wahl SM. Lacrimal gland inflammation is responsible for ocular pathology in TGF-beta 1 null mice. Am J Pathol. 1997;151:1281–8.
Nakahara M, Nagayama Y, Ichikawa T, Yu L, Eisenbarth GS, Abiru N. The effect of regulatory T-cell depletion on the spectrum of organ-specific autoimmune diseases in nonobese diabetic mice at different ages. Autoimmunity. 2011;44:504–10.
Daniels PJ, McArthur CP, Heruth DP, Rothberg PG, Pasztor L, Wang Y. Cytokine-mediated stimulation of laminin expression and cell-growth arrest in a human submandibular gland duct-cell line (HSG). Arch Oral Biol. 1999;44:603–15.
Daniels PJ, Gustafson SA, French D, Wang Y, DePond W, McArthur CP. Interferon-mediated block in cell cycle and altered integrin expression in a differentiated salivary gland cell line (HSG) cultured on Matrigel. J Interferon Cytokine Res. 2000;20:1101–9.
Wu AJ, Chen ZJ, Tsokos M, O’Connell BC, Ambudkar IS, Baum BJ. Interferon-gamma induced cell death in a cultured human salivary gland cell line. J Cell Physiol. 1996;167:297–304.
Kamachi M, Kawakami A, Yamasaki S, Hida A, Nakashima T, Nakamura H, et al. Regulation of apoptotic cell death by cytokines in a human salivary gland cell line: distinct and synergistic mechanisms in apoptosis induced by tumor necrosis factor alpha and interferon gamma. J Lab Clin Med. 2002;139:13–9.
Coursey TG, Tukler Henriksson J, Chen M, Pflugfelder SC. IFN-{gamma} influences the proliferation and differentiation of conjunctival goblet cells. ARVO Meeting Abstracts. 2014;55:2774.
Irifune K, Yokoyama A, Sakai K, Watanabe A, Katayama H, Ohnishi H, et al. Adoptive transfer of T-helper cell type 1 clones attenuates an asthmatic phenotype in mice. Eur Respir J. 2005;25:653–9.
Heller NM, Matsukura S, Georas SN, Boothby MR, Rothman PB, Stellato C, et al. Interferon-gamma inhibits STAT6 signal transduction and gene expression in human airway epithelial cells. Am J Respir Cell Mol Biol. 2004;31:573–82.
de Paiva CS, Raince JK, McClellan AJ, Shanmugam KP, Pangelinan SB, Volpe EA, et al. Homeostatic control of conjunctival mucosal goblet cells by NKT-derived IL-13. Mucosal Immunol. 2011;4:397–408.
Hoshino T, Winkler-Pickett RT, Mason AT, Ortaldo JR, Young HA. IL-13 production by NK cells: IL-13-producing NK and T cells are present in vivo in the absence of IFN-gamma. J Immunol. 1999;162:51–9.
de Paiva CS, Villarreal AL, Corrales RM, Rahman HT, Chang VY, Farley WJ, et al. Dry Eye-induced conjunctival epithelial squamous metaplasia is modulated by interferon-{gamma}. Invest Ophthalmol Vis Sci. 2007;48:2553–60.