The role of STAT proteins in the regulation of the response to the interferone α therapy in chronic hepatitis C

Česká verzia

Authors: J. Ehrmann jr. ¹; K. Aiglová ²; J. Ehrmann ²; J. Palas ³; P. Kümpel ⁴
Authors place of work: Laboratoř molekulární patologie Ústavu patologie Lékařské fakulty UP, Olomouc, přednosta doc. MUDr. M. Tichý, CSc. ¹; II. interní klinika Lékařské fakulty UP a FN, Olomouc, přednosta prof. MUDr. J. Ehrmann, CSc. ²; Oddělení patologie Slezské nemocnice, Opava, přednosta prim. MUDr. J. Palas ³; Infekční oddělení Slezské nemocnice, Opava, přednosta prim. MUDr. P. Kümpel ⁴
Published in the journal: Vnitř Lék 2006; 52(2): 167-172
Category: Review

Summary

The currently used standard treatment for chronic hepatitis C using a dual combination of IFNα/RBV is only successful in 50 % cases. With the exception of some clinical and biochemical factors, degree of inflammation (grading) and degree of fibrosis (staging), there are no other known markers which may serve as valid predictors of response to therapy. Interference of hepatitis C virus (HCV) with signaling pathways modulated by JAK-STAT, ERK 1/2, NFκB and MAP proteins is one mechanism which may influence the interaction between HCV and IFNα. These proteins regulate different cell processes such as activation of cytokines, activation of apoptosis, regulation of cell proliferation etc. Therefore, it is possible that impaired signaling or inhibition/dysregulation of some of these proteins by HCV infection may cause resistance to IFNα treatment. This review is completed by results of preliminary study the aim of which was immunohistochemical assessment and analysis of expression of STAT 2, 3 proteins, their inhibitors SOCS 2, 3 and PIAS 3 and proteins JAK 1 and ERK 1/2 in liver biopsies of 26 patients with chronic hepatitis C treated by dual combination IFNα/RBV and subsequent correlation of the results of immunohistochemical analysis (histoscore) with histological picture and clinical response to treatment. The results shows increased expression of STAT 3, STAT 2 and ERK 1 proteins and decreased expression of SOCS 3 and SOCS 2 in hepatocytes of patients with more marked inflammation and fibrosis. In patients with sustained virological response there was increased expression of SOCS 3 and JAK 1 and decreased expression of SOCS 2. Relapse was associated with increased expression of SOCS 3 and PIAS 3. However, owing to the small sample size, the results only approximated statistical significance, but we suggest that proteins of STAT family and their inhibitors SOCS and PIAS probably play an important regulatory role during response to treatment for chronic hepatitis C.

Key words:
hepatitis C - interferon α - liver biopsy - immunohistochemistry - STAT - SOCS - prediction

Zdroje

1. Zuckerman AJ, Thomas HC. Viral hepatitis. Section IV - Hepatitis C virus. 2nd ed. Oxford: Churchill Livingstome 1998; 253-358.

2. Husa P, Urbánek P, Šperl J et al. Diagnostika a léčba chronické hepatitidy C. Vnitř Lék 2005; 51: 1307-1313.

3. Manns MP, McHutchison JG, Gordon SC et al. Peginterferon α-2b plus ribavirin compared with interferon α-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358: 958-965.

4. Poynard T, McHutchison JG, Manns M et al. Impact of pegylated interferon α-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 2002; 122: 1303-1313.

5. Shiffman M, Hoffman CM, Contos MJ. A randomised controlled trial of maintenance interferon therapy for patients with chronic hepatitis C virus and persistent viremia. Gastroenterology 1999; 117: 1164-1172.

6. Husa P, Husová L. Treatment of chronic hepatitis C patients with combination of α-interferon and ribavirin, consensus and pegylated interferons. Bratisl Lék Listy 2001; 102: 248-252.

7. Crabb C. Hard-won advances spark excitement about hepatitis C. Science 2001; 294: 506-507.

8. Fontaine H, Nalpas B, Poulet B et al. Hepatitis activity index is a key factor in determining the natural history of chronic hepatitis C. Hum Pathol 2001; 32: 904-909.

9. Husa P. Jaterní biopsie u chronické infekce virem hepatitidy C - nezbytné, vhodné nebo zbytečné? Vnitř Lék 2002; 48: 1004-1006.

10. Zeuzem S. Heterogeneous virologic responce rates to interferon-based therapy in patients with chronic hepatitis C: who responds less well? Ann Intern Med 2004; 140: 370-381.

11. Capobianchi MR, Abbate I, Cappiello G et al. HCV and interferon: viral strategies for evading innate defence mechanisms in the virus-host battle. Cell Death Differ 2003; 10: S22-S24.

12. Giannini C, Brechot C. Hepatitis C virus biology. Cell Death Differ 2003; 10(Suppl): S27-S38.

13. Enomoto N, Sakuma I, Asahuna Y et al. Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus lb infection. N Engl J Med 1996; 334: 77-81.

14. Urbánek P. Infekce virem hepatitidy C. Praha: Galén 2004.

15. Darnell JE Jr. STATs and gene regulation. Science 1997; 277: 1630-1635.

16. Taniguchi T. Cytokine signaling through nonreceptor protein tyrosine kinases. Science 1995; 268: 251-255.

17. Seger R, Krebs EG. The MAPK signaling cascade. Faseb J 1995; 9: 726-735.

18. Parganas E, Wang D, Stravopodis D et al. Jak2 is essential for signaling through a variety of cytokine receptors. Cell 1998; 93: 397-409.

19. O’Shea JJ, Gadina M, Schreiber RD. Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell 2002; 109(Suppl): S121-S131.

20. Frank DA. STAT signaling in the pathogenesis and treatment of cancer. Mol Med 1999; 5: 432-456.

21. Bowman T, Garcia R, Turkson J et al. STATs in oncogenesis. Oncogene 2000; 19: 2474-2488.

22. Ward AC, Touw I, Yoshimura A. The Jak-Stat pathway in normal and perturbed hematopoiesis. Blood 2000; 95: 19-29.

23. Chapman RS, Lourenco PC, Tonner E et al. Suppresion of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3. Genes Dev 1999; 13: 2604-2616.

24. Bromberg JF, Wrzeszcynska MH, Devgan G et al. STAT3 as an oncogene. Cell 1999; 98: 295-303.

25. Kyriakis JM. Making the connection: coupling of stress-activated ERK/MAPK (extracellular-signal-regulated kinase/mitogen-activated protein kinase) core signalling modules to extracellular stimuli and biological responses. Biochem Soc Sym 1999; 64: 29-48.

26. Hilger RA, Scheulen ME, Strumberg D. The Ras-Raf-MEK-ERK pathway in the treatment of cancer. Onkologie 2002; 25: 511-518.

27. Cheng F. A critical role for STAT3 signaling in immune tolerance. Immunity 2003; 19: 425-436.

28. Wang T, Niu G, Kortylewski M et al. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nature Med 2004; 10: 48-54.

29. Boudný V, Kovařík J. JAK/STAT signaling pathways and cancer. Janus kinases/signal transducers and activators of transcription. Neoplasma 2002; 49: 349-355.

30. Ostrand-Rosenberg S, Grusby MJ, Clements VK. Cutting edge: STAT6-deficient mice have enhanced tumor immunity to primary and metastatic mammary carcinoma. J Immunol 2000; 165: 6015-6019.

31. Gouilleux-Gruart V, Gouilleux F, Desaint C et al. Stat-related transcription factors are constitutively activated in peripheral blood cells from acute leukaemia patients. Blood 1996; 87: 1692-1697.

32. Sun WH, Pabon Y, Alsayed PP et al. Interferon α resistance in a cutaneous T-cell lymphoma cell line is associated with lack of STAT1 expression. Blood 1998; 91: 570-576.

33. Kovařík J, Boudný V, Kocák I et al. Malignant melanoma associates with deficient IFN-induced STAT 1 phosphorylation. Int J Mol Med 2003; 12: 335-340.

34. Boudný V, Kocák I, Lauerová L et al. Interferon inducibility of STAT 1 activation and its prognostic significance in melanoma patients. Folia Biologica 2003; 49: 142-146.

35. Rubin-Grandis J, Drenning SD, Zeng Q et al. Constitutive activation of STAT3 signaling abrogates apoptosis in squamous cell carcinogenesis. In Vivo 1998; 97: 4227-4232.

36. Fernandes A, Hamburger AW, Gerwin BI. ErbB-2 kinase is required for constitutive STAT3 activation in malignant human lung epithelial cells. Int J Cancer 1999; 83: 564-570.

37. Watson CJ. Stat transcription factors in mammary gland development. J Mammary Gland Biol and Neoplasia 2001; 6: 115-127.

38. Nakashima K, Colamarino S, Gage FH. Embryonic stem cells: staying plastic on plastic. Nature Med 2004; 10: 23-24.

39. Steelman LS, Pohnert SC, Shelton JG et al. JAK/STAT, Raf/MEK/ERK, PI3K/akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia 2004; 18: 189-218.

40. Smaley KS. A pivotal role for ERK in the oncogenic behaviour of malignant melanoma? Int J Cancer 2003; 104: 527-532.

41. Nicosia SV, Bai W, Cheby JQ et al. Oncogenic pathways implicated in ovarian epithelial cancer. Hematol Oncol Clin North Am 2003; 17: 927-943.

42. Waris G, Tardif KD, Siddiqui A. Endoplasmic reticulum (ER) stress: hepatitis C virus induces an ER-nucleus signal transduction pathway and activates NF-κB and STAT-3. Biochem Pharmacol 2002; 64: 1425-1430.

43. Waris G, Siddiqui A. Regulatory mechanisms of viral hepatitis B and C. J Biosci 2003; 28: 311-321.

44. Gong G, Waris G, Tanveer R et al. Human hepatitis C virus NS5A protein alters intracellular calcium levels, induces oxidative stress, and activates STAT-3 and NF-κB. Proc Natl Acad Sci USA 2001; 98: 9599-9604.

45. Waris G, Turkson J, Hassanein T. Hepatitis C virus (HCV) constitutively activates STAT-3 via oxidative stress: role of STAT-3 in HCV replication. J Virol 2005; 79: 1569-1580.

46. Yoshida T, Hanada T, Tokuhisa T et al. Activation of STAT-3 by the hepatitis C virus core protein leads to cellular transformation. J Exp Med 2002; 196: 641-653.

47. Zhu H, Shang X, Terada N et al. STAT 3 induces anti-hepatitis C viral activity in liver cells. Biochem Biophys Res Com 2004; 324: 518-528.

48. Duong FHT, Filipowicz M, Tripodi M et al. Hepatitis C virus inhibits interferon signaling through up-regulation of protein phosphatase 2A. Gastroenterol 2004; 126: 263-277.

49. Melen K, Fagerlund R, Nyqvist M et al. Expression of hepatitis C virus core protein inhibits interferon-induced nuclear import of STATs. J Med Virol 2004; 73: 536-547.

50. Heim MH, Moradpour D, Blum HE. Expression of hepatitis C virus protein inhibits signal transduction through the Jak-STAT pathway. J Virol 1999; 73: 8469-8475.

51. Hosui A, Ohkawa K, Ishida H et al. Hepatitis C virus core protein differently regulates the JAK-STAT signaling pathway under interleukin-6 and interferon-gamma stimuli. J Biol Chem 2003; 278: 28562-28571.

52. Vlotides G, Sörensen AS, Kopp F et al. SOCS-1 and SOCS-3 inhibit IFN-α-induced expression of the antiviral proteins 2,5-OAS and MxA. Biochem Biophys Res Com 2004; 320: 1007-1014.

53. Imanaka K, Tamura S, Fukui K et al. Enhanced expression of suppressor of cytokine signalling-1 in the liver of chronic hepatitis C: possible involvement in resistance to interferon therapy. J Viral Hepat 2005; 12: 130-138.

54. Mallat A, Preaux AM, Blazejewski S et al. Interferon α and γ inhibit proliferation and collagen synthesis of human Ito cells in culture. Hepatology 1995; 21: 1003-1010.

55. Schuppan D, Krebs A, Bauer M et al. Hepatitis C and liver fibrosis. Cell Death Differ 2003; 10(Suppl): S59-S67.

56. Batts KP, Ludwig J. Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol 1995; 19: 1409-1417.

57. Ehrmann J Jr, Galuszková D, Ehrmann J et al. Immunohistochemical analysis of the apoptosis-related proteins, BCL-2, BAX, FAS, FAS-L and PCNA in liver biopsies of patients with chronic hepatitis B virus infection. Pathol Oncol Res 2000; 6: 130-135.

58. Lísová S, Ehrmann J, Kolek A et al. Imunohistochemická studie mechanismů apoptózy a proliferace ve sliznici tenkého střeva u celiakální sprue. Čes Slov Patol 2005; 41: 85-93.