Both IL28B gene polymorphisms and serum levels of interleukin (IL)-10, IL-12p40 and IL-18 have been reported to affect the outcome of natural and pegylated interferon and ribavirin-treated HCV infection.
Methods
To clarify their association and predictive value in treatment outcome of genotype 1 HCV- infected patients, we measured pretreatment serum IL-10, IL-12p40 and IL-18 levels using multiplex assays and determined IL28B gene polymorphisms (rs 8099917) in 52 cases with chronic hepatitis C.
Results
High baseline levels of IL-10 (P<0.001) and low levels of IL-12p40 (P<0.001) were significantly associated with a non-virological response (NVR) in our cohort. The IL28B polymorphism was tested and TT, TG or GG genotypes were found in 60%, 38% and 2% of patients, respectively, with corresponding NVR rates of 10%, 60% and 100% (P<0.001). Serum cytokine levels were significantly correlated with IL28B gene polymorphisms. When serum IL-10 levels were stratified at 5.0 pg/ml, NVR rates were 50% versus 0% (P=0.004) for the TT genotype and 87% versus 0% (P=0.001) for the TG or GG genotypes. Similarly, low IL-12p40 levels were associated with an NVR in patients with TG or GG genotypes (P=0.006). In multivariate analysis, high IL-10, low IL-12p40 and IL28B TG or GG genotypes were independently associated with an NVR.
Conclusions
Serum IL-10 and IL-12p40 levels in combination with IL28B genotype, especially G-allele carriage, are strong predictive markers of an NVR to HCV treatment with pegylated interferon and ribavirin.
References
1.
AlterH.J., PurcellR.H., ShihJ.W.Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic non-A, non-B hepatitis. N Engl J Med1989; 321: 1494–1500.
2.
KiyosawaK., SodeyamaT., TanakaE.Interrelationship of blood transfusion, non-A, non-B hepatitis and hepatocellular carcinoma: analysis by detection of antibody to hepatitis C virus. Hepatology1990; 12: 671–675.
3.
UmemuraT., IchijoT., YoshizawaK., TanakaE., KiyosawaK.Epidemiology of hepatocellular carcinoma in Japan. J Gastroenterol2009; 44Suppl 19: 102–107.
4.
MannsM.P., McHutchisonJ.G., GordonS.C.Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet2001; 358: 958–965.
5.
FriedM.W., ShiffmanM.L., ReddyK.R.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med2002; 347: 975–982.
6.
AkutaN., SuzukiF., SezakiH.Association of amino acid substitution pattern in core protein of hepatitis C virus genotype 1b high viral load and non-virological response to interferon-ribavirin combination therapy. Intervirology2005; 48: 372–380.
7.
EnomotoN., SakumaI., AsahinaY.Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. N Engl J Med1996; 334: 77–82.
8.
GeD., FellayJ., ThompsonA.J.Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature2009; 461: 399–401.
9.
SuppiahV., MoldovanM., AhlenstielG.IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet2009; 41: 1100–1104.
10.
TanakaY., NishidaN., SugiyamaM.Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet2009; 41: 1105–1109.
11.
RauchA., KutalikZ., DescombesP.Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology2010; 138: 1338–1345.
12.
ThomasD.L., ThioC.L., MartinM.P.Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature2009; 461: 798–801.
13.
DonnellyR.P., SheikhF., KotenkoS.V., DickensheetsH.The expanded family of class II cytokines that share the IL-10 receptor-2 (IL-10R2) chain. J Leukoc Biol2004; 76: 314–321.
14.
FiorentinoD.F., BondM.W., MosmannT.R.Two types of mouse T helper cell. I V. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med1989; 170: 2081–2095.
15.
FiorentinoD.F., ZlotnikA., VieiraP.IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J Immunol1991; 146: 3444–3451.
16.
McGeachyM.J., Bak-JensenK.S., ChenY.TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol2007; 8: 1390–1397.
17.
StumhoferJ.S., SilverJ.S., LaurenceA.Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat Immunol2007; 8: 1363–1371.
18.
Edwards-SmithC.J., JonssonJ.R., PurdieD.M., BansalA., ShorthouseC., PowellE.E.Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis C to interferon alfa. Hepatology1999; 30: 526–530.
19.
YeeL.J., TangJ., GibsonA.W., KimberlyR., Van LeeuwenD.J., KaslowR.A.Interleukin 10 polymorphisms as predictors of sustained response in antiviral therapy for chronic hepatitis C infection. Hepatology2001; 33: 708–712.
20.
KnappS., HennigB.J., FrodshamA.J.Interleukin-10 promoter polymorphisms and the outcome of hepatitis C virus infection. Immunogenetics2003; 55: 362–369.
21.
MorganT.R., LambrechtR.W., BonkovskyH.L.DNA polymorphisms and response to treatment in patients with chronic hepatitis C: results from the HALT-C trial. J Hepatol2008; 49: 548–556.
22.
YonedaS., UmemuraT., KatsuyamaY.Association of serum cytokine levels with treatment response to pegylated interferon and ribavirin therapy in genotype 1 chronic hepatitis C patients. J Infect Dis2011; 203: 1087–1095.
23.
UmemuraT., WangR.Y., SchechterlyC., ShihJ.W., KiyosawaK., AlterH.J.Quantitative analysis of anti-hepatitis C virus antibody-secreting B cells in patients with chronic hepatitis C. Hepatology2006; 43: 91–99.
24.
UmemuraT., ZenY., HamanoH., KawaS., NakanumaY., KiyosawaK.Immunoglobin G4-hepatopathy: association of immunoglobin G4-bearing plasma cells in liver with autoimmune pancreatitis. Hepatology2007; 46: 463–471.
25.
KatoN., HijikataM., OotsuyamaY.Molecular cloning of the human hepatitis C virus genome from Japanese patients with non-A, non-B hepatitis. Proc Natl Acad Sci U S A1990; 87: 9524–9528.
26.
HondaM., SakaiA., YamashitaT.Hepatic ISG expression is associated with genetic variation in interleukin 28B and the outcome of IFN therapy for chronic hepatitis C. Gastroenterology2010; 139: 499–509.
27.
UrbanT.J., ThompsonA.J., BradrickS.S.IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C. Hepatology2010; 52: 1888–1896.
28.
RossolS., MarinosG., CarucciP., SingerM.V., WilliamsR., NaoumovN.V.Interleukin-12 induction of Th1 cytokines is important for viral clearance in chronic hepatitis B. J Clin Invest1997; 99: 3025–3033.
29.
QuirogaJ.A., MartinJ., NavasS., CarrenoV.Induction of interleukin-12 production in chronic hepatitis C virus infection correlates with the hepatocellular damage. J Infect Dis1998; 178: 247–251.
30.
Marín-SerranoE., Rodriguez-RamosC., DiazF., Martin-HerreraL., Giron-GonzalezJ.A.Modulation of the anti-inflammatory interleukin 10 and of proapoptotic IL-18 in patients with chronic hepatitis C treated with interferon alpha and ribavirin. J Viral Hepat2006; 13: 230–234.
31.
SaraivaM., O'GarraA.The regulation of IL-10 production by immune cells. Nat Rev Immunol2010; 10: 170–181.
32.
TrinchieriG.Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol1995; 13: 251–276.
33.
MegjugoracN.J., GallagherG.E., GallagherG.Modulation of human plasmacytoid DC function by IFN-lambda1 (IL-29). J Leukoc Biol2009; 86: 1359–1363.
34.
LiuB.S., JanssenH.L., BoonstraA.IL-29 and IFNα differ in their ability to modulate IL-12 production by TLR-activated human macrophages, and exhibit differential regulation of the IFNγ receptor expression. Blood2011; 117: 2385–2395.
