臺灣博碩士論文加值系統

IL-10 family cytokine對於保護組織、避免組織因為感染及發炎反應而受到破壞相當重要。其中IL-10可抑制發炎反應並且也可抑制肝纖維化的發生。而IL-22則是對於上皮組織的平衡、修復以及傷口癒合相當重要。目前的研究顯示IL-10及IL-22在免疫反應的調控上皆扮演了重要的角色，特別是在肝臟的發炎反應中，兩者皆可有效的減緩肝臟的發炎反應。IL-10及IL-22對於許多不同的自體免疫疾病亦有抑制的效果。原發性膽道硬化症 (Primary Biliary Cirrhosis，PBC) 為一種因免疫反應引起肝內小膽管的發炎及損壞的肝臟自體免疫疾病，導致慢性膽汁鬱積，最終會造成肝纖維化與肝硬化。本研究探討IL-10及IL-22對於肝臟自體免疫疾病 PBC的影響。由於AAV (adeno-associated virus)僅會引起輕微的發炎反應，且可長久的表達其所攜帶的基因，因此可作為良好的載體。我們利用攜帶IL-10及IL-22基因的AAV以尾靜脈注射方式打入以2-OA-OVA/α-GalCer致敏的PBC小鼠體內，觀察PBC小鼠的自體抗體、肝臟單核細胞浸潤及病理變化。我們發現給予IL-10的PBC小鼠肝臟中的B cells數量下降、Foxp3+ CD4 T cells的數量上升，肝臟中的granulomas數目及MMP-9的表現降低。而給予IL-22的PBC小鼠肝臟單核細胞數顯著下降，尤其是T cells及B cells。IL-10 也許可透過降低B cells的數目及增加肝臟中Tregs的數量以減緩PBC的發炎反應，或透過降低granulomas的形成及減少MMP-9的表現以抑制fibrosis。而IL-22則可減緩PBC所引起的肝臟發炎細胞浸潤，特別是T cells及B cells。因此IL-10及IL-22均會降低肝臟自體免疫疾病PBC的發炎反應。

IL-10 family cytokines are essential for the prevention of tissue damage caused by excessive inflammatory responses as well as maintaining the homeostasis of tissue epithelial layers. IL-10 is an anti-inflammatory and anti-fibrotic cytokine. IL-22 preserves tissue integrity with enhanced wound-healing and tissue repair activities. Both IL-10 and IL-22 are important in controlling the inflammatory response, especially in hepatitis. In addition IL-10 and IL-22 also have the protective effects in the variety of autoimmune diseases. Primary biliary cirrhosis (PBC) is a liver autoimmune disease, characterized by the immune mediated infiltration and destruction of the bile duct, which leads to cholestasis, fibrosis, and finally, cirrhosis. Our specific aim is to investigate the effects of IL-10 and IL-22 on the regulation of PBC. Because of the minute immune response and the long-term expression of the gene, adeno-associated virus (AAV) is a good vector for gene transfer. In this study, mouse IL-10 and IL-22 expressing AAV were injected to 2-OA-OVA/α-GC immunized mice and PBC features including serum anti-mitochondrial antibodies (AMA) titer, liver mononuclear cells infiltration and the histopathology in these cytokine expressed mice were then examined. Our results showed that administration of IL-10 decreased B cells but increased Foxp3+ CD4 T cells in the liver of 2-OA-OVA/α-GC immunized PBC mice. Moreover, reduced granulomas and MMP-9 expression were observed in the liver of IL-10 injected PBC mice. IL-22 administration reduced the liver mononuclear cells, especially T cells and B cells in 2-OA-OVA/α-GC immunized PBC mice. These results suggested that IL-10 in PBC might inhibit liver inflammation by decreasing B cells and increasing Foxp3+ regulatory T cells. In addition, IL-10 may suppress liver fibrosis by reducing the granulomas formation and MMP-9 expression. IL-22 could ameliorate liver inflammation by decreasing T cell and B cell infiltration in PBC mice. Taken together, our study demonstrated the down-regulatory effects of IL-10 and IL-22 on PBC.

致謝 i
摘要 ii
Abstract iii
縮寫對照表 v
目錄 vi
圖目錄 ix
第一章 研究背景 1
1.1 IL-10家族之細胞激素 (IL-10 Family Cytokine) 1
1.1.1 IL-10及其訊號傳遞 1
1.1.2 IL-10之分泌細胞及作用細胞 2
1.1.3 IL-10之生理功能 2
1.1.4 IL-10在發炎反應及自體免疫疾病中的角色 2
1.1.5 IL-10對於肝臟的保護作用 3
1.1.6 IL-22及其訊號傳遞 4
1.1.7 IL-22之分泌細胞及作用細胞 4
1.1.8 IL-22之生理功能 4
1.1.9 IL-22在發炎反應及自體免疫疾病中的角色 5
1.1.10 IL-22對於肝臟的保護作用 5
1.2 Adeno-associated virus (AAV) 6
1.2.1 AAV之基因及其功能 6
1.2.2 AAV作為基因表現之載體 6
1.2.3 AAV所引起的免疫反應 7
1.3 肝臟及其免疫系統 7
1.3.1 原發性膽道硬化症 (Primary Biliary Cirrhosis，PBC) 8
1.3.2 PBC的致病機轉 8
1.3.3 PBC之免疫反應 9
1.3.4 2-OA-induced PBC小鼠動物模式 10
1.4 研究目的 10
第二章 實驗材料與方法 11
2.1製備帶有IL-10及IL-22之pAAV-IRES-GFP 11
2.2 3H-Thymidine incorporation assay 11
2.3西方墨點法 (Western blotting assay) 12
2.4 AAV組裝 (cotransfection pAAV-IRES-GFP、pAAV-DJ及pHelper) 12
2.5 AAV純化 13
2.6 AAV濃縮及定量 13
2.7 Polymerase Chain Reaction (PCR) 13
2.8 實驗用小鼠 14
2.9 AAV注射及PBC小鼠模式 14
2.10 血清樣本收集 15
2.11 小鼠肝臟灌流與病理切片製作 15
2.12 小鼠肝臟單核細胞的純化 15
2.13 流式細胞儀 (flow cytometry)分析細胞表面抗原 15
2.14 以ELISA測定PBC小鼠血清中的anti-mPDC-E2 IgM及IgG 16
2.15 以ELISA測定血清中的細胞激素 17
2.16 組織及細胞RNA之萃取 17
2.17 RNA反轉錄成cDNA 18
2.18 以即時定量反轉錄聚合&;#37238;連鎖反應偵測特定基因之mRNA表現 18
2.19 Granulomas之分析及計算 19
2.20 繪圖與統計分析 19
第三章 實驗結果 20
3.1 製備pAAV-mIL-10及pAAV-mIL-22並確認其功能 20
3.2 AAV以尾靜脈注射的方式打入小鼠，其所攜帶之細胞激素可在小鼠肝臟表現至少10週 20
3.3 當PBC小鼠體內表現高量之IL-10時，肝臟B cells數量下降但CD4 T cells及Foxp3+ CD4 T cells數目升高 21
3.4 當PBC小鼠體內表現高量之IL-10時，可減少肝臟granulomas的形成及纖維化相關基因的表現 22
3.5 當PBC小鼠體內表現較高的IL-22時，可發現肝臟單核細胞數、B cells數以及T cells數量皆降低 23
3.6 當PBC小鼠體內表現高量之IL-22時，可減少肝臟中較大的granulomas的形成 24
第四章 討論 25
圖 31
參考文獻 55
附錄 64

1.Hofmann, S.R., et al., Biological properties and regulation of IL-10 related cytokines and their contribution to autoimmune disease and tissue injury. Clin Immunol, 2012. 143(2): p. 116-27.
2.Sa, S.M., et al., The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis. J Immunol, 2007. 178(4): p. 2229-40.
3.Uze, G. and D. Monneron, IL-28 and IL-29: newcomers to the interferon family. Biochimie, 2007. 89(6-7): p. 729-34.
4.Fiorentino, D.F., M.W. Bond, and T.R. Mosmann, Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med, 1989. 170(6): p. 2081-95.
5.Levy, Y. and J.C. Brouet, Interleukin-10 prevents spontaneous death of germinal center B cells by induction of the bcl-2 protein. J Clin Invest, 1994. 93(1): p. 424-8.
6.Moore, K.W., et al., Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol, 2001. 19: p. 683-765.
7.Ouyang, W., et al., Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu Rev Immunol, 2011. 29: p. 71-109.
8.Iyer, S.S. and G. Cheng, Role of interleukin 10 transcriptional regulation in inflammation and autoimmune disease. Crit Rev Immunol, 2012. 32(1): p. 23-63.
9.Tournoy, K.G., J.C. Kips, and R.A. Pauwels, Endogenous interleukin-10 suppresses allergen-induced airway inflammation and nonspecific airway responsiveness. Clin Exp Allergy, 2000. 30(6): p. 775-83.
10.Tanaka, Y., et al., Effect of IL-10 on collagen-induced arthritis in mice. Inflamm Res, 1996. 45(6): p. 283-8.
11.Park, Y.B., et al., Elevated interleukin-10 levels correlated with disease activity in systemic lupus erythematosus. Clin Exp Rheumatol, 1998. 16(3): p. 283-8.
12.Melgar, S., et al., Over-expression of interleukin 10 in mucosal T cells of patients with active ulcerative colitis. Clin Exp Immunol, 2003. 134(1): p. 127-37.
13.Lopatin, U., et al., Increases in circulating and lymphoid tissue interleukin-10 in autoimmune lymphoproliferative syndrome are associated with disease expression. Blood, 2001. 97(10): p. 3161-70.
14.Mirakian, R., L.J. Hammond, and G.F. Bottazzo, TH1 and TH2 cytokine control of thyrocyte survival in thyroid autoimmunity. Nat Immunol, 2001. 2(5): p. 371.
15.Di Marco, R., et al., Concanavalin A-induced hepatitis in mice is prevented by interleukin (IL)-10 and exacerbated by endogenous IL-10 deficiency. Autoimmunity, 1999. 31(2): p. 75-83.
16.Louis, H., et al., Production and role of interleukin-10 in concanavalin A-induced hepatitis in mice. Hepatology, 1997. 25(6): p. 1382-9.
17.Louis, H., et al., Hepatoprotective role of interleukin 10 in galactosamine/lipopolysaccharide mouse liver injury. Gastroenterology, 1997. 112(3): p. 935-42.
18.Dumoutier, L., J. Louahed, and J.C. Renauld, Cloning and characterization of IL-10-related T cell-derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9. J Immunol, 2000. 164(4): p. 1814-9.
19.Sabat, R., W. Ouyang, and K. Wolk, Therapeutic opportunities of the IL-22-IL-22R1 system. Nat Rev Drug Discov, 2014. 13(1): p. 21-38.
20.Lejeune, D., et al., Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. Pathways that are shared with and distinct from IL-10. J Biol Chem, 2002. 277(37): p. 33676-82.
21.Wolk, K., et al., Cutting edge: immune cells as sources and targets of the IL-10 family members? J Immunol, 2002. 168(11): p. 5397-402.
22.Rutz, S., C. Eidenschenk, and W. Ouyang, IL-22, not simply a Th17 cytokine. Immunol Rev, 2013. 252(1): p. 116-32.
23.Wolk, K., et al., IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis. Eur J Immunol, 2006. 36(5): p. 1309-23.
24.Andoh, A., et al., Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology, 2005. 129(3): p. 969-84.
25.Ikeuchi, H., et al., Expression of interleukin-22 in rheumatoid arthritis: potential role as a proinflammatory cytokine. Arthritis Rheum, 2005. 52(4): p. 1037-46.
26.Zheng, Y., et al., Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature, 2007. 445(7128): p. 648-51.
27.Geboes, L., et al., Proinflammatory role of the Th17 cytokine interleukin-22 in collagen-induced arthritis in C57BL/6 mice. Arthritis Rheum, 2009. 60(2): p. 390-5.
28.Sugimoto, K., et al., IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest, 2008. 118(2): p. 534-44.
29.Zenewicz, L.A., et al., Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity, 2007. 27(4): p. 647-59.
30.Radaeva, S., et al., Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation. Hepatology, 2004. 39(5): p. 1332-42.
31.Wahl, C., et al., IL-22-dependent attenuation of T cell-dependent (ConA) hepatitis in herpes virus entry mediator deficiency. J Immunol, 2009. 182(8): p. 4521-8.
32.Ren, X., B. Hu, and L.M. Colletti, IL-22 is involved in liver regeneration after hepatectomy. Am J Physiol Gastrointest Liver Physiol, 2010. 298(1): p. G74-80.
33.Yang, L., et al., Amelioration of high fat diet induced liver lipogenesis and hepatic steatosis by interleukin-22. J Hepatol, 2010. 53(2): p. 339-47.
34.Daya, S. and K.I. Berns, Gene therapy using adeno-associated virus vectors. Clin Microbiol Rev, 2008. 21(4): p. 583-93.
35.Kotin, R.M., et al., Site-specific integration by adeno-associated virus. Proc Natl Acad Sci U S A, 1990. 87(6): p. 2211-5.
36.Srivastava, A., E.W. Lusby, and K.I. Berns, Nucleotide sequence and organization of the adeno-associated virus 2 genome. J Virol, 1983. 45(2): p. 555-64.
37.Pereira, D.J., D.M. McCarty, and N. Muzyczka, The adeno-associated virus (AAV) Rep protein acts as both a repressor and an activator to regulate AAV transcription during a productive infection. J Virol, 1997. 71(2): p. 1079-88.
38.Steinbach, S., et al., Assembly of adeno-associated virus type 2 capsids in vitro. J Gen Virol, 1997. 78 ( Pt 6): p. 1453-62.
39.Schnepp, B.C., et al., Characterization of adeno-associated virus genomes isolated from human tissues. J Virol, 2005. 79(23): p. 14793-803.
40.Zaiss, A.K., et al., Differential activation of innate immune responses by adenovirus and adeno-associated virus vectors. J Virol, 2002. 76(9): p. 4580-90.
41.Wang, L., et al., Cross-presentation of adeno-associated virus serotype 2 capsids activates cytotoxic T cells but does not render hepatocytes effective cytolytic targets. Hum Gene Ther, 2007. 18(3): p. 185-94.
42.Murphy, S.L., et al., Prolonged susceptibility to antibody-mediated neutralization for adeno-associated vectors targeted to the liver. Mol Ther, 2008. 16(1): p. 138-45.
43.Brockstedt, D.G., et al., Induction of immunity to antigens expressed by recombinant adeno-associated virus depends on the route of administration. Clin Immunol, 1999. 92(1): p. 67-75.
44.Manno, C.S., et al., Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med, 2006. 12(3): p. 342-7.
45.Crispe, I.N., The liver as a lymphoid organ. Annu Rev Immunol, 2009. 27: p. 147-63.
46.Concepcion, A.R. and J.F. Medina, Approaches to the pathogenesis of primary biliary cirrhosis through animal models. Clin Res Hepatol Gastroenterol, 2012. 36(1): p. 21-8.
47.Bittencourt, P.L., et al., Prevalence of immune disturbances and chronic liver disease in family members of patients with primary biliary cirrhosis. J Gastroenterol Hepatol, 2004. 19(8): p. 873-8.
48.Selmi, C., et al., Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology, 2004. 127(2): p. 485-92.
49.Gershwin, M.E., et al., Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology, 2005. 42(5): p. 1194-202.
50.Bogdanos, D.P., et al., The role of E. coli infection in the pathogenesis of primary biliary cirrhosis. Dis Markers, 2010. 29(6): p. 301-11.
51.Bogdanos, D.P., et al., Primary biliary cirrhosis is characterized by IgG3 antibodies cross-reactive with the major mitochondrial autoepitope and its Lactobacillus mimic. Hepatology, 2005. 42(2): p. 458-65.
52.Amano, K., et al., Chemical xenobiotics and mitochondrial autoantigens in primary biliary cirrhosis: identification of antibodies against a common environmental, cosmetic, and food additive, 2-octynoic acid. J Immunol, 2005. 174(9): p. 5874-83.
53.Wakabayashi, K., et al., Loss of tolerance in C57BL/6 mice to the autoantigen E2 subunit of pyruvate dehydrogenase by a xenobiotic with ensuing biliary ductular disease. Hepatology, 2008. 48(2): p. 531-40.
54.Leung, P.S., et al., Induction of primary biliary cirrhosis in guinea pigs following chemical xenobiotic immunization. J Immunol, 2007. 179(4): p. 2651-7.
55.Mao, T.K., et al., Altered monocyte responses to defined TLR ligands in patients with primary biliary cirrhosis. Hepatology, 2005. 42(4): p. 802-8.
56.Kikuchi, K., et al., Bacterial CpG induces hyper-IgM production in CD27(+) memory B cells in primary biliary cirrhosis. Gastroenterology, 2005. 128(2): p. 304-12.
57.Chuang, Y.H., et al., Increased killing activity and decreased cytokine production in NK cells in patients with primary biliary cirrhosis. J Autoimmun, 2006. 26(4): p. 232-40.
58.Shimoda, S., et al., HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases. J Exp Med, 1995. 181(5): p. 1835-45.
59.Kita, H., et al., Identification of HLA-A2-restricted CD8(+) cytotoxic T cell responses in primary biliary cirrhosis: T cell activation is augmented by immune complexes cross-presented by dendritic cells. J Exp Med, 2002. 195(1): p. 113-23.
60.Lan, R.Y., et al., Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis. Hepatology, 2006. 43(4): p. 729-37.
61.Odin, J.A., et al., Bcl-2-dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis. J Clin Invest, 2001. 108(2): p. 223-32.
62.Lleo, A., et al., Biliary apotopes and anti-mitochondrial antibodies activate innate immune responses in primary biliary cirrhosis. Hepatology, 2010. 52(3): p. 987-98.
63.Wu, S.J., et al., Innate immunity and primary biliary cirrhosis: activated invariant natural killer T cells exacerbate murine autoimmune cholangitis and fibrosis. Hepatology, 2011. 53(3): p. 915-25.
64.McClure, C., et al., Production and titering of recombinant adeno-associated viral vectors. J Vis Exp, 2011(57): p. e3348.
65.Taga, K. and G. Tosato, IL-10 inhibits human T cell proliferation and IL-2 production. J Immunol, 1992. 148(4): p. 1143-8.
66.Xie, M.H., et al., Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R. Journal of Biological Chemistry, 2000. 275(40): p. 31335-31339.
67.Turhan, N., et al., Hepatic granulomas: a clinicopathologic analysis of 86 cases. Pathol Res Pract, 2011. 207(6): p. 359-65.
68.Kossakowska, A.E., et al., Altered balance between matrix metalloproteinases and their inhibitors in experimental biliary fibrosis. Am J Pathol, 1998. 153(6): p. 1895-902.
69.Kong, X., et al., Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice. Hepatology, 2012. 56(3): p. 1150-9.
70.Chuah, C., et al., Cellular and chemokine-mediated regulation in schistosome-induced hepatic pathology. Trends Parasitol, 2014. 30(3): p. 141-50.
71.de Waal Malefyt, R., et al., Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med, 1991. 174(5): p. 1209-20.
72.Hirano, T., et al., Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature, 1986. 324(6092): p. 73-6.
73.Itoh, K. and S. Hirohata, The role of IL-10 in human B cell activation, proliferation, and differentiation. J Immunol, 1995. 154(9): p. 4341-50.
74.Henningsson, L., et al., Disease-dependent local IL-10 production ameliorates collagen induced arthritis in mice. PLoS One, 2012. 7(11): p. e49731.
75.Fukushima, N., et al., Characterization of recombinant monoclonal IgA anti-PDC-E2 autoantibodies derived from patients with PBC. Hepatology, 2002. 36(6): p. 1383-92.
76.Malmborg, A.C., et al., Penetration and co-localization in MDCK cell mitochondria of IgA derived from patients with primary biliary cirrhosis. J Autoimmun, 1998. 11(5): p. 573-80.
77.Groux, H., et al., A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature, 1997. 389(6652): p. 737-42.
78.Battaglia, M., et al., Rapamycin and interleukin-10 treatment induces T regulatory type 1 cells that mediate antigen-specific transplantation tolerance. Diabetes, 2006. 55(1): p. 40-9.
79.Meiron, M., et al., CXCL12 (SDF-1alpha) suppresses ongoing experimental autoimmune encephalomyelitis by selecting antigen-specific regulatory T cells. J Exp Med, 2008. 205(11): p. 2643-55.
80.Asnagli, H., et al., Type 1 regulatory T cells specific for collagen-type II as an efficient cell-based therapy in arthritis. Arthritis Res Ther, 2014. 16(3): p. R115.
81.Sakaguchi, S., et al., Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev, 2001. 182: p. 18-32.
82.McNally, A.K. and J.M. Anderson, Macrophage fusion and multinucleated giant cells of inflammation. Adv Exp Med Biol, 2011. 713: p. 97-111.
83.Shrivastava, P. and T. Bagchi, IL-10 modulates in vitro multinucleate giant cell formation in human tuberculosis. PLoS One, 2013. 8(10): p. e77680.
84.Cyktor, J.C., et al., IL-10 inhibits mature fibrotic granuloma formation during Mycobacterium tuberculosis infection. J Immunol, 2013. 190(6): p. 2778-90.
85.Almadi, M.A., et al., New insights into gastrointestinal and hepatic granulomatous disorders. Nat Rev Gastroenterol Hepatol, 2011. 8(8): p. 455-66.
86.You, Z., et al., The immunopathology of liver granulomas in primary biliary cirrhosis. J Autoimmun, 2012. 39(3): p. 216-21.
87.Lee, R.G., et al., Granulomas in primary biliary cirrhosis: a prognostic feature. Gastroenterology, 1981. 81(6): p. 983-6.
88.Han, Y.P., et al., Essential role of matrix metalloproteinases in interleukin-1-induced myofibroblastic activation of hepatic stellate cell in collagen. J Biol Chem, 2004. 279(6): p. 4820-8.
89.Yu, Q. and I. Stamenkovic, Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev, 2000. 14(2): p. 163-76.
90.Tan, T.K., et al., Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage. Lab Invest, 2013. 93(4): p. 434-49.
91.Prakobwong, S., et al., Involvement of MMP-9 in peribiliary fibrosis and cholangiocarcinogenesis via Rac1-dependent DNA damage in a hamster model. Int J Cancer, 2010. 127(11): p. 2576-87.
92.Houssiau, F.A., et al., Serum interleukin 10 titers in systemic lupus erythematosus reflect disease activity. Lupus, 1995. 4(5): p. 393-5.
93.Cua, D.J., et al., Transgenic interleukin 10 prevents induction of experimental autoimmune encephalomyelitis. J Exp Med, 1999. 189(6): p. 1005-10.
94.Cannella, B., et al., IL-10 fails to abrogate experimental autoimmune encephalomyelitis. J Neurosci Res, 1996. 45(6): p. 735-46.
95.Shaw, M.K., et al., Local delivery of interleukin 4 by retrovirus-transduced T lymphocytes ameliorates experimental autoimmune encephalomyelitis. J Exp Med, 1997. 185(9): p. 1711-4.
96.Pennline, K.J., E. Roque-Gaffney, and M. Monahan, Recombinant human IL-10 prevents the onset of diabetes in the nonobese diabetic mouse. Clin Immunol Immunopathol, 1994. 71(2): p. 169-75.
97.Lee, M.S., et al., IL-10 is necessary and sufficient for autoimmune diabetes in conjunction with NOD MHC homozygosity. J Exp Med, 1996. 183(6): p. 2663-8.
98.Sasaki, M., et al., Naturally-occurring regulatory T cells are increased in inflamed portal tracts with cholangiopathy in primary biliary cirrhosis. J Clin Pathol, 2007. 60(10): p. 1102-7.
99.Huang, Y.H., et al., Hydrodynamics-based transfection of rat interleukin-10 gene attenuates porcine serum-induced liver fibrosis in rats by inhibiting the activation of hepatic stellate cells. Int J Mol Med, 2014.
100.Pan, H.F., et al., Emerging role of interleukin-22 in autoimmune diseases. Cytokine Growth Factor Rev, 2013. 24(1): p. 51-7.
101.Zhao, J., et al., Pathological functions of interleukin-22 in chronic liver inflammation and fibrosis with hepatitis B virus infection by promoting T helper 17 cell recruitment. Hepatology, 2014. 59(4): p. 1331-42.
102.Mielke, L.A., et al., Retinoic acid expression associates with enhanced IL-22 production by gammadelta T cells and innate lymphoid cells and attenuation of intestinal inflammation. J Exp Med, 2013. 210(6): p. 1117-24.
103.Xue, J., D.T. Nguyen, and A. Habtezion, Aryl hydrocarbon receptor regulates pancreatic IL-22 production and protects mice from acute pancreatitis. Gastroenterology, 2012. 143(6): p. 1670-80.
104.Farahani, R., et al., Cytokines (interleukin-9, IL-17, IL-22, IL-25 and IL-33) and asthma. Adv Biomed Res, 2014. 3: p. 127.
105.Ke, Y., et al., IL-22-induced regulatory CD11b+ APCs suppress experimental autoimmune uveitis. J Immunol, 2011. 187(5): p. 2130-9.
106.Gelebart, P., et al., Interleukin 22 signaling promotes cell growth in mantle cell lymphoma. Transl Oncol, 2011. 4(1): p. 9-19.
107.Justa, S., X. Zhou, and S. Sarkar, Endogenous IL-22 plays a dual role in arthritis: regulation of established arthritis via IFN-gamma responses. PLoS One, 2014. 9(3): p. e93279.
108.Kawata, K., et al., Identification of potential cytokine pathways for therapeutic intervention in murine primary biliary cirrhosis. PLoS One, 2013. 8(9): p. e74225.