We investigated short-term alterations in plasma in-rently used in the treatments of chronic hepatitis B 3, terleukin-6 (IL-6), interleukin-1b (IL-1b), and tumor neand C and for the treatment of some malignant tucrosis factor a (TNF-a) levels induced by interferon alfa mors. 7 (IFN-a) injection in 18 patients with chronic hepatitis C.
IFN-a induces various biological responses, such as
A single intramuscular injection of human recombinant fever and general malaise. Whereas some of these re-IFN-a 2a (6 million units [MU]) significantly increased sponses could be caused by the direct effects of IFN-a the plasma IL-6 level 6 hours after the injection (P itself, others may be attributed to the effects of cytokine Γ΅ .05). On the other hand, the IFN-a injection did not interactions. Interleukin-6 (IL-6), interleukin-1b (ILaffect the plasma TNF-a and IL-1b levels. Polymerase 1b), and tumor necrosis factor a (TNF-a) are multifuncchain reaction (PCR) analysis showed accumulation of tional cytokines that are induced in inflammatory re-IL-6 gene transcripts in peripheral blood mononuclear cells (PBMC) after IFN-a injection, indicating that IFN-sponses. 8 However, little is known about the in vivo a enhances IL-6 production at the messenger RNA level. modulation of these cytokines by IFN-a. IFN-a therapy The induction of IL-6 by IFN-a was completely supfor chronic hepatitis C is a good model in which to study pressed by the intravenous administration of gabexate these cytokine interactions. In this study, we examined mesilate (GM), a serine protease inhibitor. The mechathe short-term effects of IFN-a on IL-6, IL-1b, and nism whereby GM suppresses the elevation in circulat-TNF-a in patients with chronic hepatitis C. ing IL-6 levels seems to be the inhibition of IL-6 produc-Current interests in cytokine research are now being tion at the messenger RNA level. Elevations of both directed to the modulation of circulating cytokines, and serum C-reactive protein (CRP) levels and body tempersuppression of the excess production of cytokines in ature after GM-suppressed IFN-a injection suggest that various human pathophysiological conditions is now the administration of GM, by suppressing IL-6 production, may attenuate the IL-6-related responses induced under investigation. 10 The use of protease inhibitors by IFN-a injection. In conclusion, we found that IL-6 was has been shown to be a useful strategy for inhibiting induced by IFN-a in vivo, and that this induction was the production of circulating TNF-a 11,12 and IL-1b. 13,14 completely abrogated by the administration of GM. Our In a previous study, we found that gabexate mesilate results indicate that serine protease inhibitors may be (GM), a serine protease inhibitor, suppressed the elevauseful for inhibiting IL-6-relating responses. (HEPATOLtion of serum IL-6 levels after transcatheter arterial OGY 1996;23:669-675.) embolization for the treatment of hepatocellular carcinoma. Our observations suggested that GM is a po-Interferon (IFN) is recognized as a potent antiviral, tent IL-6 inhibitor in vivo. antiproliferative, and immunomodulatory agent. 1, Another aim of this study was to examine whether Three major IFNs have been identified and are in clini-GM also suppressed IL-6 production in hepatitis C vical use. One of these, interferon alfa (IFN-a), is currus (HCV)-infected patients treated with IFN-a, and to further clarify the effect of GM on IL-6 gene expression in peripheral blood mononuclear cells (PBMC).