Ribavirin upregulates interleukin-12 receptor and induces T cell differentiation towards type 1 in chronic hepatitis C.
OBJECTIVE
The mechanisms of ribavirin as an immune modulator have not been fully revealed, contrary to its clinical benefit in chronic hepatitis C. Recently, host immune defense, especially cytotoxic T lymphocytes and T helper cells, have been considered to be closely related to the pathophysiology of chronic viral hepatitis. The aim of the present study was to evaluate the function of ribavirin in cellular immunity.


METHODS
Peripheral blood mononuclear cells and total RNA were prepared from chronic hepatitis C patients. To evaluate the polarization of T helper cells, we performed intracellular cytokine assay and quantified the production of key cytokines. mRNA levels of interleukin-12 receptor (IL-12R), interferon (IFN)-gamma and interleukin-4 (IL-4) were measured by real time reverse transcription-polymerase chain reaction (RT-PCR).


RESULTS
The population of T helper 1 cells increased significantly both in mitogen and hepatitis C virus (HCV) core protein stimulated cells with 0.1 microg/mL of ribavirin. However, the population of T helper 2 cells did not seem to be affected by ribavirin. The level of IL-12R beta2 chain mRNA was also upregulated to 130% after 24 h incubation with 0.1 microg/mL ribavirin (P = 0.037), whereas the beta1 chain did not change significantly under these conditions. In addition, 0.1 microg/mL ribavirin could upregulate the levels of IFN-gamma or IL-4 mRNA in some cases.


CONCLUSIONS
Ribavirin, perhaps by acting directly on CD4+ T cells, induces T cell differentiation towards type 1, depending on the upregulated signal of the IL-12/IL-12R pathway.
Shiina
Masaaki
M
Department of Gastroenterology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. shiina@wb3.so-net.ne.jp
Kobayashi
Koju
K
Satoh
Hiroko
H
Niitsuma
Hirofumi
H
Ueno
Yoshiyuki
Y
Shimosegawa
Tooru
T
D000998:Antiviral Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012333:RNA, Messenger / Q000097:blood; D018123:Receptors, Interleukin / Q000096:biosynthesis*; D053707:Receptors, Interleukin-12; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012254:Ribavirin / Q000494:pharmacology*; D018709:Statistics, Nonparametric; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects* / Q000276:immunology
D000998:Antiviral Agents; C508438:IL12RB1 protein, human; C508439:IL12RB2 protein, human; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D012254:Ribavirin