干擾素是脊椎動物在防禦病毒感染時首先分泌的一種細胞激素。受感染的細胞本身會誘發干擾素的合成和分泌。干擾素在臨床上常用來治療某些特定的惡性腫瘤。依據干擾素所結合的受體不同，主要可分成結合至IFNARI和IFNARII的第一型干擾素：干擾素α和β屬之；以及結合至IFNGR的第二型干擾素：干擾素γ屬之。而干擾素的訊息傳遞路徑是經由JAK/STAT活化下游的基因表現，並造成細胞生長受到抑制。第一個主題是研究STAT6在第一型干擾素抑制細胞生長作用中的重要性。在先前的研究指出，第一型干擾素誘導的STAT6在Daudi和B細胞中具有抗增殖作用。因此，STAT6可能在第一型干擾素所引起的抑制細胞生長活性中扮演著重要的角色。我們經由對於干擾素敏感與具有抗性的Daudi細胞（DS 和DR）來研究STAT6在抗增殖活性中的作用。在第一型干擾素反應下DS細胞顯著增加STAT6 mRNA和蛋白表達，但在DR細胞卻無差異。而STAT6基因敲除實驗中則發現顯著降低兩種細胞對於干擾素的敏感性。為偵測第一型干擾素活化的STAT6所調控之下游基因及其功能之重要性，因此我們將第一型干擾素處理後的Daudi細胞以染色質免疫沉澱法反應再經由高通量晶片篩選分析。從晶片分析數據中發現干擾素誘導活化的STAT6能促使DS細胞中的Sp1表現增加並抑制BCL6表現，然而在DR細胞中卻未有明確的影響。同樣的在抑制STAT6表達後則發現能同時降低DS和DR細胞中Sp1和BCL6 mRNA和蛋白表現。除此之外，我們也發現Sp1和BCL6表達在STAT2缺陷型RST2細胞中不會受干擾素影響，但隨著STAT2的活性回復，Sp1和BCL6的調控也恢復對於干擾素的敏感性，這表明STAT2對於STAT6的活化是很重要的。這些結果顯示第一型干擾素的抗增殖作用是通過STAT2介導活化STAT6，並進一步調節Sp1和BCL6而引起的分子機制。
第二個研究的主題則是探討在膽道閉鎖疾病中干擾素伽碼（IFN-γ）誘導微核糖核酸155 (miR-155) 在炎症反應中的調控機制。微核糖核酸（miRNA）是約22個核苷酸的RNA，其負責調節真核生物中的基因表達和炎症反應。膽道閉鎖 (BA) 是兒童慢性肝病的最常見形式，為兒科肝移植的主要適應症。首先我們偵測人類和小鼠膽道閉鎖及健康對照組的肝組織中miR-155和SOCS1基因的表達。並於膽道細胞實驗中發現IFN-γ能誘導miR-155、發炎因子和趨化因子的表達。此外，經由抑制miR-155的表達以蛋白質分析IFN-γ誘導信號傳導路徑的影響。在BA組織切片和小鼠膽管細胞中觀察到miR-155會受到IFN-γ誘導而明顯表達。miR-155通過結合至SOCS1 mRNA而使得 SOCS1表達減少。IFN-γ則通過Jak / Stat途徑活化miR-155表達並促使其下游Stat1和發炎因子表現，然而miR-155表達若下降，則會顯著抑制這些發炎因子的mRNA以及Stat1的蛋白表達。總而言之，我們的研究結果顯示miR-155透過結合至SOCS1而參與調節IFN-γ信息路徑，進而調控下游發炎因子，此分子機制對於BA的治療也許具有潛在的可能性。

The interferon (IFN) system is the first line of defence against virus infection in the vertebrates. The infection itself triggers IFN synthesis and secretion. According to the differences of binding receptor. Binds to receptor of IFNAR1 and IFNAR2 chains : type I, which includes IFN-α and IFN-β, and binds to receptor of IFNGR : type II; comprising IFN-γ. In the first study is to evaluate the importance of STAT6 in the anti-proliferative effects of type I interferon. Type I IFN-induced STAT6 has been shown to have anti-proliferative effects in Daudi and B cells. IFN-sensitive (DS) and IFN-resistant (DR) subclones of Daudi cells were used to study the role of STAT6 in the anti-proliferative activities. Type I IFN significantly increased STAT6 mRNA and protein expression in DS but not DR cells. STAT6 knockdown significantly reduced the sensitivity to IFN in both cell lines. The molecular targets and functional importance of IFN-activated STAT6 were performed by chromatin immunoprecipitation-on-chip (ChIP-on-chip) experiments in type I IFN-treated Daudi cells. Two target genes (Sp1 and BCL6) were selected from the ChIP-on-chip data. IFN-induced STAT6 activation led to Sp1 upregulation and BCL6 downregulation in DS cells, with only minimal effects in DR cells. siRNA inhibition of STAT6 expression resulted in decreased Sp1 and BCL6 mRNA and protein levels in both DS and DR cells. IFN treatment did not increase Sp1 and BCL6 expression in a STAT2-deficient RST2 cell line, and this effect was mitigated by plasmid overexpression of STAT2, indicating that STAT2 is important for STAT6 activation. These results suggest that STAT6 plays an important role in regulating Sp1 and BCL6 through STAT2 to exert the anti-proliferative effects of type I IFN.
In the second study is to evaluate the roles of miRNA (miR)-155 on the interferon-γ (IFN-γ)-induced response in biliary atresia (BA). MicroRNAs (miRNAs) are ∼22-nucleotide long RNAs that negatively regulate gene expression and inflammatory responses in eukaryotes. Biliary atresia (BA) is the most common form of pediatric chronic liver disease and a leading indication for pediatric liver transplantation. The expression of miR-155 and the suppressor of cytokine signaling 1 (SOCS1) gene in human and mice liver tissues of BA and healthy controls was evaluated. IFN-γ-induced expression of miR-155, inflammatory cytokines and chemokines was determined in bile duct cells. A miR-155 inhibitor was used to determine the influence in the IFN-γ-induced signaling pathway by western blot analysis. A strong up-regulation of miR-155 expression was observed in BA histologic sections and mouse bile duct cells treated with IFN-γ. miR-155 down-regulated SOCS1 protein expression by targeting its mRNA. Up-regulation of miR-155 expression by IFN-γ in bile duct cells led to the activation of Stat1 and inflammatory cytokines through the Jak/Stat pathway, whereas targeted inhibition of miR-155 expression by anti-miRNA oligonucleotides significantly decreased the mRNA or protein expression levels of these inflammatory cytokines and Stat1. Overall, our results suggest that miR-155 regulates the IFN-γ signaling pathway by targeting SOCS1 expression and may be a potential target in BA therapy.

1. Pfeffer LM, Dinarello CA, Herberman RB, Williams BR, Borden EC, Bordens R, Walter MR, Nagabhushan TL, Trotta PP, Pestka S. 1998. Biological properties of recombinant alpha-interferons: 40th anniversary of the discovery of interferons. Cancer Res 58:2489-2499.
2. Caraglia M, Marra M, Pelaia G, Maselli R, Caputi M, Marsico SA, Abbruzzese A. 2005. Alpha-interferon and its effects on signal transduction pathways. J Cell Physiol 202:323-335.
3. Kotenko SV, Pestka S. 2000. Jak-Stat signal transduction pathway through the eyes of cytokine class II receptor complexes. Oncogene 19:2557-2565.
4. Leonard WJ. 2001. Role of Jak kinases and STATs in cytokine signal transduction. Int J Hematol 73:271-277.
5. Kubo K, Aoki H, Nanba H. 1994. Anti-diabetic activity present in the fruit body of Grifola frondosa (Maitake). I. Biological & pharmaceutical bulletin 17:1106-1110.
6. O'Shea JJ. 1997. Jaks, STATs, cytokine signal transduction, and immunoregulation: are we there yet? Immunity 7:1-11.
7. Schindler C, Shuai K, Prezioso VR, Darnell JE, Jr. 1992. Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science 257:809-813.
8. Schindler C, X.-Y. Fu, T. Improta, R. Aebersold, and J. E. Darnell. 1992. Proteins of transcription factor ISGF-3: one gene encodes the 91- and 84-kDa
ISGF-3 proteins that are activated by interferon a. Proc. Natl. Acad. Sci. USA 89:7836.
9. Wurster AL, Tanaka T, Grusby MJ. 2000. The biology of Stat4 and Stat6. Oncogene 19:2577-2584.
10. Yang CH, Shi W, Basu L, Murti A, Constantinescu SN, Blatt L, Croze E, Mullersman JE, Pfeffer LM. 1996. Direct association of STAT3 with the IFNAR-1 chain of the human type I interferon receptor. The Journal of biological chemistry 271:8057-8061.
11. Meinke A, Barahmand-Pour F, Wohrl S, Stoiber D, Decker T. 1996. Activation of different Stat5 isoforms contributes to cell-type-restricted signaling in response to interferons. Molecular and cellular biology 16:6937-6944.
12. Cho SS, Bacon CM, Sudarshan C, Rees RC, Finbloom D, Pine R, O'Shea JJ. 1996. Activation of STAT4 by IL-12 and IFN-alpha: evidence for the involvement of ligand-induced tyrosine and serine phosphorylation. Journal of immunology 157:4781-4789.
13. Bruns HA, Kaplan MH. 2006. The role of constitutively active Stat6 in leukemia and lymphoma. Crit Rev Oncol Hematol 57:245-253.
14. Ansel KM, Djuretic I, Tanasa B, Rao A. 2006. Regulation of Th2 differentiation and Il4 locus accessibility. Annu Rev Immunol 24:607-656.
15. Ostrand-Rosenberg S, Grusby MJ, Clements VK. 2000. Cutting Edge: STAT6-Deficient Mice Have Enhanced Tumor Immunity to Primary and Metastatic Mammary Carcinoma. The Journal of Immunology 165:6015-6019.
16. Ostrand-Rosenberg S, Sinha P, Clements V, Dissanayake SI, Miller S, Davis C, Danna E. 2004. Signal transducer and activator of transcription 6 (Stat6) and CD1: inhibitors of immunosurveillance against primary tumors and metastatic disease. Cancer Immunol Immunother 53:86-91.
17. Kacha AK, Fallarino F, Markiewicz MA, Gajewski TF. 2000. Spontaneous Rejection of Poorly Immunogenic P1.HTR Tumors by Stat6-Deficient Mice. The Journal of Immunology 165:6024-6028.
18. Suske G. 1999. The Sp-family of transcription factors. Gene 238:291-300.
19. Pan D, Courey AJ. 1992. The same dorsal binding site mediates both activation and repression in a context-dependent manner. The EMBO journal 11:1837-1842.
20. Bin L, Howell MD, Kim BE, Streib JE, Hall CF, Leung DY. 2011. Specificity protein 1 is pivotal in the skin's antiviral response. J Allergy Clin Immunol 127:430-438 e431-432.
21. Albagli-Curiel O. 2003. Ambivalent role of BCL6 in cell survival and transformation. Oncogene 22:507-516.
22. Artiga MJ, Saez AI, Romero C, Sanchez-Beato M, Mateo MS, Navas C, Mollejo M, Piris MA. 2002. A short mutational hot spot in the first intron of BCL-6 is associated with increased BCL-6 expression and with longer overall survival in large B-cell lymphomas. American Journal of Pathology 160:1371-1380.
23. Hurtz C, Hatzi K, Cerchietti L, Braig M, Park E, Kim YM, Herzog S, Ramezani-Rad P, Jumaa H, Muller MC, Hofmann WK, Hochhaus A, Ye BH, Agarwal A, Druker BJ, Shah NP, Melnick AM, Muschen M. 2011. BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia. J Exp Med 208:2163-2174.
24. Gallavotti A, Zhao Q, Kyozuka J, Meeley RB, Ritter MK, Doebley JF, Pe ME, Schmidt RJ. 2004. The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature 432:630-635.
25. Yildiz M, Li H, Bernard D, Amin NA, Ouillette P, Jones S, Saiya-Cork K, Parkin B, Jacobi K, Shedden K, Wang S, Chang AE, Kaminski MS, Malek SN. 2015. Activating STAT6 mutations in follicular lymphoma. Blood 125:668-679.
26. Ritz O, Guiter C, Castellano F, Dorsch K, Melzner J, Jais JP, Dubois G, Gaulard P, Moller P, Leroy K. 2009. Recurrent mutations of the STAT6 DNA binding domain in primary mediastinal B-cell lymphoma. Blood 114:1236-1242.
27. Hebenstreit D, Wirnsberger G, Horejs-Hoeck J, Duschl A. 2006. Signaling mechanisms, interaction partners, and target genes of STAT6. Cytokine & growth factor reviews 17:173-188.
28. Georas SN, Cumberland JE, Burke TF, Chen R, Schindler U, Casolaro V. 1998. Stat6 inhibits human interleukin-4 promoter activity in T cells. Blood 92:4529-4538.
29. Schindler C, Kashleva H, Pernis A, Pine R, Rothman P. 1994. STF-IL-4: a novel IL-4-induced signal transducing factor. The EMBO journal 13:1350-1356.
30. Kohler I, Rieber EP. 1993. Allergy-associated I epsilon and Ec epsilon receptor II (CD23b) genes activated via binding of an interleukin-4-induced transcription factor to a novel responsive element. European journal of immunology 23:3066-3071.
31. Du Z, Fan M, Kim JG, Eckerle D, Lothstein L, Wei L, Pfeffer LM. 2009. Interferon-resistant Daudi cell line with a Stat2 defect is resistant to apoptosis induced by chemotherapeutic agents. The Journal of biological chemistry 284:27808-27815.
32. Lindner DJ, Kalvakolanu DV, Borden EC. 1997. Increasing effectiveness of interferon-alpha for malignancies. Semin Oncol 24:S9-99-S99-104.
33. McLaughlin P. 1996. The role of interferon in the therapy of malignant lymphoma. Biomed Pharmacother 50:140-148.
34. Willmes C, Adam C, Alb M, Volkert L, Houben R, Becker JC, Schrama D. 2012. Type I and II IFNs inhibit Merkel cell carcinoma via modulation of the Merkel cell polyomavirus T antigens. Cancer Res 72:2120-2128.
35. Darnell JE, Jr., Kerr IM, Stark GR. 1994. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264:1415-1421.
36. Copeland NG, Gilbert DJ, Schindler C, Zhong Z, Wen Z, Darnell JE, Jr., Mui AL, Miyajima A, Quelle FW, Ihle JN, et al. 1995. Distribution of the mammalian Stat gene family in mouse chromosomes. Genomics 29:225-228.
37. Darnell JE, Jr. 1997. STATs and gene regulation. Science 277:1630-1635.
38. Gupta S, Jiang M, Pernis AB. 1999. IFN-alpha activates Stat6 and leads to the formation of Stat2:Stat6 complexes in B cells. Journal of immunology 163:3834-3841.
39. Fasler-Kan E, Pansky A, Wiederkehr M, Battegay M, Heim MH. 1998. Interferon-alpha activates signal transducers and activators of transcription 5 and 6 in Daudi cells. Eur J Biochem 254:514-519.
40. Wan L, Lin CW, Lin YJ, Sheu JJ, Chen BH, Liao CC, Tsai Y, Lin WY, Lai CH, Tsai FJ. 2008. Type I IFN induced IL1-Ra expression in hepatocytes is mediated by activating STAT6 through the formation of STAT2: STAT6 heterodimer. J Cell Mol Med 12:876-888.
41. Elo LL, Jarvenpaa H, Tuomela S, Raghav S, Ahlfors H, Laurila K, Gupta B, Lund RJ, Tahvanainen J, Hawkins RD, Oresic M, Lahdesmaki H, Rasool O, Rao KV, Aittokallio T, Lahesmaa R. 2010. Genome-wide profiling of interleukin-4 and STAT6 transcription factor regulation of human Th2 cell programming. Immunity 32:852-862.
42. Ricardo-Gonzalez RR, Red Eagle A, Odegaard JI, Jouihan H, Morel CR, Heredia JE, Mukundan L, Wu D, Locksley RM, Chawla A. 2010. IL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity. Proceedings of the National Academy of Sciences of the United States of America 107:22617-22622.
43. Wei M, Liu B, Gu Q, Su L, Yu Y, Zhu Z. 2013. Stat6 cooperates with Sp1 in controlling breast cancer cell proliferation by modulating the expression of p21(Cip1/WAF1) and p27 (Kip1). Cell Oncol (Dordr) 36:79-93.
44. Black AR, Black JD, Azizkhan-Clifford J. 2001. Sp1 and kruppel-like factor family of transcription factors in cell growth regulation and cancer. J Cell Physiol 188:143-160.
45. Marin M, Karis A, Visser P, Grosveld F, Philipsen S. 1997. Transcription factor Sp1 is essential for early embryonic development but dispensable for cell growth and differentiation. Cell 89:619-628.
46. Lou Z, O'Reilly S, Liang H, Maher VM, Sleight SD, McCormick JJ. 2005. Down-regulation of overexpressed sp1 protein in human fibrosarcoma cell lines inhibits tumor formation. Cancer Res 65:1007-1017.
47. Deniaud E, Baguet J, Mathieu AL, Pages G, Marvel J, Leverrier Y. 2006. Overexpression of Sp1 transcription factor induces apoptosis. Oncogene 25:7096-7105.
48. Chuang JY, Wu CH, Lai MD, Chang WC, Hung JJ. 2009. Overexpression of Sp1 leads to p53-dependent apoptosis in cancer cells. Int J Cancer 125:2066-2076.
49. Albagli O, Lantoine D, Quief S, Quignon F, Englert C, Kerckaert JP, Montarras D, Pinset C, Lindon C. 1999. Overexpressed BCL6 (LAZ3) oncoprotein triggers apoptosis, delays S phase progression and associates with replication foci. Oncogene 18:5063-5075.
50. Yamochi T, Kaneita Y, Akiyama T, Mori S, Moriyama M. 1999. Adenovirus-mediated high expression of BCL-6 in CV-1 cells induces apoptotic cell death accompanied by down-regulation of BCL-2 and BCL-X(L). Oncogene 18:487-494.
51. Shaffer AL, Yu X, He Y, Boldrick J, Chan EP, Staudt LM. 2000. BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity 13:199-212.
52. Mikita T, Daniel C, Wu P, Schindler U. 1998. Mutational analysis of the STAT6 SH2 domain. The Journal of biological chemistry 273:17634-17642.
53. Schindler U, Wu P, Rothe M, Brasseur M, McKnight SL. 1995. Components of a Stat recognition code: evidence for two layers of molecular selectivity. Immunity 2:689-697.
54. Leung S, Qureshi SA, Kerr IM, Darnell JE, Jr., Stark GR. 1995. Role of STAT2 in the alpha interferon signaling pathway. Molecular and cellular biology 15:1312-1317.
55. Alexander, W.S., Starr, R., Fenner, J.E., Scott, C.L., Handman, E., Sprigg, N.S., Corbin, J.E., Cornish, A.L., Darwiche, R., Owczarek, C.M., Kay, T.W., Nicola, N. A., Hertzog, P.J., Metcalf, D. and Hilton, D.J. 1999. SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell 98: 597-608
56. Balistreri, W.F., Grand, R., Hoofnagle, J.H., Suchy, F.J., Ryckman, F.C., Perlmutter, D.H. and Sokol, R.J. 1996. Biliary atresia: current concepts and research directions. Summary of a symposium. Hepatology 23: 1682-1692
57. Bezerra, J.A., Tiao, G., Ryckman, F.C., Alonso, M., Sabla, G.E., Shneider, B., Sokol, R.J. and Aronow, B.J. 2002. Genetic induction of proinflammatory immunity in children with biliary atresia. Lancet 360: 1653-1659
58. Briscoe, J., Rogers, N.C., Witthuhn, B.A., Watling, D., Harpur, A.G., Wilks, A.F., Stark, G.R., Ihle, J.N. and Kerr, I.M. 1996. Kinase-negative mutants of JAK1 can sustain interferon-gamma-inducible gene expression but not an antiviral state. EMBO. J. 15: 799-809
59. Carvalho, E., Liu, C., Shivakumar, P., Sabla, G., Aronow, B. and Bezerra, J.A. (2005) Analysis of the biliary transcriptome in experimental biliary atresia. Gastroenterology 129: 713-717
60. Costinean, S., Sandhu, S.K., Pedersen, I.M., Tili, E., Trotta, R., Perrotti, D., Ciarlariello, D., Neviani, P., Harb, J., Kauffman, L.R., Shidham, A. and Croce, C.M. 2009. Src homology 2 domain-containing inositol-5-phosphatase and CCAAT enhancer-binding protein β are targeted by miR-155 in B cells of Eμ-MiR-155 transgenic mice. Blood 114: 1374-1382
61. Darnell, J.E., Jr., Kerr, I.M. and Stark, G.R. 1994. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264: 1415-1421
62. Désiré, N., Zeng, Q. and Yang, X. 2014. Adjuvant effects of di-(2-Ethylhexyl) phthalate on the inflammatory process in glucose homeostatic organs in mice fed fat or carbohydrate diet. Adapt. Med. 6: 178-184
63. Dorsett, Y., McBride, K.M., Jankovic, M., Gazumyan, A., Thai, T.H., Robbiani, D. F., Di Virgilio, M., Reina San-Martin, B., Heidkamp, G., Schwickert, T.A., Eisenreich, T., Rajewsky, K. and Nussenzweig, M.C. 2008. MicroRNA-155 suppresses activation-induced cytidine deaminase-mediated Myc-Igh translocation. Immunity 28: 630-638
64. Eis, P.S., Tam, W., Sun, L., Chadburn, A., Li, Z., Gomez, M.F., Lund, E. and Dahlberg, J.E. 2005. Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc. Natl. Acad. Sci. USA 102: 3627-3632
65. Faraoni, I., Antonetti, F.R., Cardone, J. and Bonmassar, E. 2009. miR-155 gene: a typical multifunctional microRNA. Biochim. Biophys. Acta 1792: 497-505
66. Frucht, D.M., Fukao, T., Bogdan, C., Schindler, H., O'Shea, J.J. and Koyasu, S. 2001. IFN-gamma production by antigen-presenting cells: mechanisms emerge. Trends Immunol. 22: 556-560
67. Fukao, T., Frucht, D.M., Yap, G., Gadina, M., O'Shea, J.J. and Koyasu, S. 2001. Inducible expression of Stat4 in dendritic cells and macrophages and its critical role in innate and adaptive immune responses. J. Immunol. 166: 4446-4455
68. Gessani, S. and Belardelli, F. (1998) IFN-γ expression in macrophages and its possible biological significance. Cytokine Growth Factor Rev. 9: 117-123
69. Hartley, J.L., Davenport, M. and Kelly, D.A. 2009. Biliary atresia. Lancet 374: 1704-1713
70. Hochrein, H., Shortman, K., Vremec, D., Scott, B., Hertzog, P. and O'Keeffe, M. 2001. Differential production of IL-12, IFN-α, and IFN-γ by mouse dendritic cell subsets. J. Immunol. 166: 5448-5455
71. Jiang, S., Zhang, H.W., Lu, M.H., He, X.H., Li, Y., Gu, H., Liu, M.F. and Wang, E.D. 2010. MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene. Cancer Res. 70: 3119-3127
72. Kanda, N., Shimizu, T., Tada, Y. and Watanabe, S. 2007. IL-18 enhances IFN-γ-induced production of CXCL9, CXCL10, and CXCL11 in human keratinocytes. Eur. J. Immunol. 37: 338-350
73. Kaplan, D.H., Greenlund, A.C., Tanner, J.W., Shaw, A.S. and Schreiber, R.D. 1996. Identification of an interferon-γ receptor α chain sequence required for JAK-1 binding. J. Biol. Chem. 271: 9-12
74. Kutty, R.K., Nagineni, C.N., Samuel, W., Vijayasarathy, C., Hooks, J.J. and Redmond, T.M. 2010. Inflammatory cytokines regulate microRNA-155 expression in human retinal pigment epithelial cells by activating JAK/STAT pathway. Biochem. Biophys. Res. Commun. 402: 390-395
75. Lawrie, C.H. 2013. MicroRNAs and lymphomagenesis: a functional review. Brit. J. Haematol. 160: 571-581
76. Liou, H.L., Shih, C.C., Chao, Y.F., Lin, N.T., Lai, S.T., Wang, S.H. and Chen, H.I. 2012. Inflammatory response to colloids compared to crystalloid priming in cardiac surgery patients with cardiopulmonary bypass. Chinese J. Physiol. 55: 210-218
77. Marine, J.C., Topham, D.J., McKay, C., Wang, D., Parganas, E., Stravopodis, D., Yoshimura, A. and Ihle, J.N. 1999. SOCS1 deficiency causes a lymphocyte-dependent perinatal lethality. Cell 98: 609-616.
78. McLoughlin, R.M., Witowski, J., Robson, R.L., Wilkinson, T.S., Hurst, S.M., Williams, A.S., Williams, J.D., Rose-John, S., Jones, S.A. and Topley, N. 2003. Interplay between IFN-γ and IL-6 signaling governs neutrophil trafficking and apoptosis during acute inflammation. J. Clin. Invest. 112: 598-607
79. O'Connell, R.M., Taganov, K.D., Boldin, M.P., Cheng, G. and Baltimore, D. 2007. MicroRNA-155 is induced during the macrophage inflammatory response. Proc. Natl. Acad. Sci. USA 104: 1604-1609
80. Ohi, R. 2001. Surgery for biliary atresia. Liver 21: 175-182
81. Pakarinen, M.P. and Rintala, R.J. 2011. Surgery of biliary atresia. Scand. J. Surg. 100: 49-53
82. Sayed, D. and Abdellatif, M. 2011. MicroRNAs in development and disease. Physiol. Rev. 91: 827-887
83. Schindler, C. and Darnell, J.E., Jr. 1995. Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. Annu. Rev. Biochem. 64: 621-651
84. Schindler, H., Lutz, M.B., Rollinghoff, M. and Bogdan, C. 2001. The production of IFN-γ by IL-12/IL-18-activated macrophages requires STAT4 signaling and is inhibited by IL-4. J. Immunol. 166: 3075-3082
85. Schroder, K., Hertzog, P.J., Ravasi, T. and Hume, D.A. 2004. Interferon- γ: an overview of signals, mechanisms and functions. J. Leukoc. Biol. 75: 163-189
86. Sen, G.C. 2001. Viruses and interferons. Annu. Rev. Microbiol. 55: 255-281
87. Shen, W.J., Dong, R., Chen, G. and Zheng, S. 2014. microRNA-222 modulates liver fibrosis in a murine model of biliary atresia. Biochem. Biophys. Res. Commun. 446: 155-159
88. Shivakumar, P., Campbell, K.M., Sabla, G.E., Miethke, A., Tiao, G., McNeal, M.M., Ward, R.L. and Bezerra, J.A. 2004. Obstruction of extrahepatic bile ducts by lymphocytes is regulated by IFN-γ in experimental biliary atresia. J. Clin. Invest. 114: 322-329
89. Vigorito, E., Perks, K.L., Abreu-Goodger, C., Bunting, S., Xiang, Z., Kohlhaas, S., Das, P.P., Miska, E.A., Rodriguez, A., Bradley, A., Smith, K.G., Rada, C., Enright, A.J., Toellner, K.M., Maclennan, I.C. and Turner, M. 2007. microRNA-155 regulates the generation of immunoglobulin class-switched plasma cells. Immunity 27: 847-859
90. Xia, W., Li, D.W., Xiang, L., Chang, J.J., Xia, Z.L. and Han, E.J. 2015. Neuroprotective effects of an aqueous extract of Futokadsura stem in an Aβ-induced Alzheimer's disease-like rat model. Chinese J. Physiol. 58: 104-113
91. Yang, Y., Liu, Y.J., Tang, S.T., Yang, L., Yang, J., Cao, G.Q., Zhang, J.H., Wang, X.X. and Mao, Y.Z. 2013. Elevated Th17 cells accompanied by decreased regulatory T cells and cytokine environment in infants with biliary atresia. Pediatr. Surg. Int. 29: 1249-1260
92. Zahm, A.M., Hand, N.J., Boateng, L.A. and Friedman, J.R. 2012. Circulating microRNA is a biomarker of biliary atresia. J. Pediatr. Gastroenterol Nutr. 55: 366-369
93. Zhang, J.G., Farley, A., Nicholson, S.E., Willson, T.A., Zugaro, L.M., Simpson, R.J., Moritz, R.L., Cary, D., Richardson, R., Hausmann, G., Kile, B.J., Kent, S.B., Alexander, W.S., Metcalf, D., Hilton, D.J., Nicola, N.A. and Baca, M. 1999. The conserved SOCS box motif in suppressors of cytokine signaling binds to elongins B and C and may couple bound proteins to proteasomal degradation. Proc. Natl. Acad. Sci. USA 96: 2071-2076