Differential interferon signaling in liver lobule and portal area cells under treatment for chronic hepatitis C.
OBJECTIVE
The mechanisms of treatment resistance to interferon (IFN) and ribavirin (Rib) combination therapy for hepatitis C virus (HCV) infection are not known. This study aims to gain insight into these mechanisms by exploring hepatic gene expression before and during treatment.


METHODS
Liver biopsy was performed in 50 patients before therapy and repeated in 30 of them 1week after initiating combination therapy. The cells in liver lobules (CLL) and the cells in portal areas (CPA) were obtained from 12 patients using laser capture microdissection (LCM).


RESULTS
Forty-three patients were infected with genotype 1 HCV, 20 of who were viral responders (genotype 1-Rsp) with treatment outcome of SVR or TR, while 23 were non-responders (genotype 1-nonRsp) with NR. Only seven patients were infected with genotype 2. Before treatment, the expression of IFN and Rib-stimulated genes (IRSGs), apoptosis-associated genes, and immune reaction gene pathways was greater in genotype 1-nonRsp than in Rsp. During treatment, IRSGs were induced in genotype 1-Rsp, but not in nonRsp. IRSG induction was irrelevant in genotype 2-Rsp and was mainly impaired in CLL but not in CPA. Pathway analysis revealed that many immune regulatory pathways were induced in CLL from genotype 1-Rsp, while growth factors related to angiogenesis and fibrogenesis were more induced in CPA from genotype 1-nonRsp.


CONCLUSIONS
Impaired IRSGs induction in CLL reduces the sensitivity to treatment for genotype 1 HCV infection. CLL and CPA in the liver might be differentially involved in treatment resistance. These findings could be useful for the improvement of therapy for HCV infection.
Honda
Masao
M
Department of Gastroenterology, Kanazawa University, Graduate School of Medicine, Kanazawa, Japan.
Nakamura
Mikiko
M
Tateno
Makoto
M
Sakai
Akito
A
Shimakami
Tetsuro
T
Shirasaki
Takayoshi
T
Yamashita
Tatsuya
T
Arai
Kuniaki
K
Yamashita
Taro
T
Sakai
Yoshio
Y
Kaneko
Shuichi
S
D000328:Adult; D000368:Aged; D004359:Drug Therapy, Combination; D005260:Female; D020869:Gene Expression Profiling; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D011994:Recombinant Proteins; D012254:Ribavirin / Q000008:administration & dosage*; D015398:Signal Transduction
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin