Induction of interleukin‐6 by interferon alfa and its abrogation by a serine protease inhibitor in patients with chronic hepatitis C

We investigated short‐term alterations in plasma interleukin‐6 (IL‐6), interleukin‐1β (IL‐1β), and tumor necrosis factor α (TNF‐α) levels induced by interferon alfa (IFN‐α) injection in 18 patients with chronic hepatitis C. A single intramuscular injection of human recombinant IFN‐α 2a (6 million units [MU]) significantly increased the plasma IL‐6 level 6 hours after the injection (P < .05). On the other hand, the IFN‐α injection did not affect the plasma TNF‐α and IL‐lβ levels. Polymerase chain reaction (PCR) analysis showed accumulation of IL‐6 gene transcripts in peripheral blood mononuclear cells (PBMC) after IFN‐α injection, indicating that IFN‐α enhances IL‐6 production at the messenger RNA level. The induction of IL‐6 by IFN‐α was completely suppressed by the intravenous administration of gabexate mesilate (GM), a serine protease inhibitor. The mechanism whereby GM suppresses the elevation in circulating IL‐6 levels seems to be the inhibition of IL‐6 production at the messenger RNA level. Elevations of both serum C‐reactive protein (CRP) levels and body temperature after GM‐suppressed IFN‐α injection suggest that the administration of GM by suppressing IL‐6 production, may attenuate the IL‐6‐related responses induced by IFN‐α injection. In conclusion, we found that IL‐6 was induced by IFN‐α in vivo, and that this induction was completely abrogated by the administration of GM. Our results indicate that serine protease inhibitors may be useful for inhibiting IL‐6‐relating responses.

[1]  Mark A. Murcko,et al.  Structure and mechanism of interleukin-lβ converting enzyme , 1994, Nature.

[2]  M. Gerhart,et al.  Protection against a lethal dose of endotoxin by an inhibitor of tumour necrosis factor processing , 1994, Nature.

[3]  E. Proietti,et al.  Injection of mice with antibody to interferon enhances the growth of transplantable murine tumors , 1983, The Journal of experimental medicine.

[4]  T. Merigan,et al.  Effect of human leukocyte interferon on hepatitis B virus infection in patients with chronic active hepatitis. , 1976, The New England journal of medicine.

[5]  D. Kalvakolanu,et al.  Gene induction by interferons: functional complementation between trans-acting factors induced by alpha interferon and gamma interferon , 1990, Molecular and cellular biology.

[6]  P. Scuderi.  Suppression of human leukocyte tumor necrosis factor secretion by the serine protease inhibitor p-toluenesulfonyl-L-arginine methyl ester (TAME). , 1989, Journal of immunology.

[7]  T. Hirano,et al.  Excessive production of interleukin 6/B cell stimulatory factor‐2 in rheumatoid arthritis , 1988, European journal of immunology.

[8]  B. Barlogie,et al.  Treatment of multiple myeloma with recombinant alpha-interferon. , 1986, Blood.

[9]  Robert C. Thompson,et al.  Interleukin-1 receptor antagonist reduces mortality from endotoxin shock , 1990, Nature.

[10]  G. Alexander,et al.  Spontaneous production of tumour necrosis factor α and interleukin-1β during interferon-α treatment of chronic HBV infection , 1990, The Lancet.

[11]  K C Zoon,et al.  Interferons and their actions. , 1987, Annual review of biochemistry.

[12]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[13]  Eugene R. Schiff,et al.  Treatment of Chronic Hepatitis C with Recombinant Interferon Alfa , 1989 .

[14]  P. Cameron,et al.  Identification of a monocyte specific pre-interleukin 1 beta convertase activity. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[15]  L. Moldawer,et al.  Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor alpha in vitro and in vivo. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[16]  J. Hoofnagle,et al.  Treatment of chronic non-A,non-B hepatitis with recombinant human alpha interferon. A preliminary report. , 1986, The New England journal of medicine.

[17]  T. Ishikawa,et al.  Serum interleukin 6 levels in patients with chronic hepatitis B. , 1991, The American journal of gastroenterology.

[18]  L. G. Thijs,et al.  Increased plasma levels of interleukin-6 in sepsis [see comments] , 1989 .

[19]  H. Baumann,et al.  IL-6 modulates the synthesis of a specific set of acute phase plasma proteins in vivo. , 1989, Journal of immunology.

[20]  A. Ogata,et al.  Systemic production of interleukin-6 following acute inflammation. , 1993, Biochemical and biophysical research communications.

[21]  B. Williams,et al.  Identification and characterization of an interferon (IFN)-stimulated response element-IFN-stimulated gene factor 3-independent signaling pathway for IFN-α , 1994 .

[22]  R. Ulevitch,et al.  Participation of tumor necrosis factor in the mediation of gram negative bacterial lipopolysaccharide-induced injury in rabbits. , 1988, The Journal of clinical investigation.

[23]  T. Kishimoto,et al.  The biology of interleukin-6. , 1989, Blood.

[24]  A. H. Drummond,et al.  Processing of tumour necrosis factor-α precursor by metalloproteinases , 1994, Nature.

[25]  B. Beutler,et al.  Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1 , 1986, The Journal of experimental medicine.

[26]  S. Raziuddin,et al.  Cytokine profile of viral and autoimmune chronic active hepatitis. , 1993, The Journal of allergy and clinical immunology.

[27]  T. Hirano,et al.  Regulation of BSF-2/IL-6 production by human mononuclear cells. Macrophage-dependent synthesis of BSF-2/IL-6 by T cells. , 1988, Journal of immunology.

[28]  Xin-Yuan Fu.  A transcription factor with SH2 and SH3 domains is directly activated by an interferon α-induced cytoplasmic protein tyrosine kinase(s) , 1992, Cell.

[29]  A. Albino,et al.  Induction of growth factor RNA expression in human malignant melanoma: markers of transformation. , 1991, Cancer research.

[30]  K. Cantell,et al.  DOUBLE-BLIND STUDY OF LEUCOCYTE INTERFERON ADMINISTRATION IN CHRONIC HBsAg-POSITIVE HEPATITIS , 1980, The Lancet.

[31]  F. Epstein,et al.  Rheumatoid arthritis. Pathophysiology and implications for therapy. , 1990, The New England journal of medicine.

[32]  G. Stark,et al.  The protein tyrosine kinase JAK1 complements defects in interferon-α/β and -γ signal transduction , 1993, Nature.

[33]  T. Taniguchi,et al.  Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin , 1986, Nature.

[34]  Kevin J. Tracey,et al.  Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia , 1987, Nature.

[35]  G. Alexander,et al.  Increased production of tumour necrosis factor alpha in chronic hepatitis B virus infection. , 1991, Journal of hepatology.

[36]  A. Billiau,et al.  Cytokines and their interactions with other inflammatory mediators in the pathogenesis of sepsis and septic shock , 1991, European journal of clinical investigation.

[37]  C. Dinarello,et al.  Anticytokine strategies in the treatment of the systemic inflammatory response syndrome. , 1993, JAMA.

[38]  T. Hirano,et al.  Recombinant human B cell stimulatory factor 2 (BSF‐2/IFN‐β2) regulates β‐fibrinogen and albumin mRNA levels in Fao‐9 cells , 1987 .