Interleukin-32: A New Proinflammatory Cytokine Involved in Hepatitis C Virus-Related Liver Inflammation and Fibrosis

Hepatology. 2011 Jun;53(6):1819-29. doi: 10.1002/hep.24285. Epub 2011 May 14.

Abstract

Interleukin 32 (IL-32) is a recently described proinflammatory cytokine that activates p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB), thereby inducing proinflammatory cytokines such as IL-1β and tumor necrosis factor alpha (TNF-α). We investigated the role of IL-32 in patients with chronic hepatitis C virus (HCV) infection. Steady-state hepatic messenger RNA (mRNA) levels of IL-32 were determined in a cohort of 90 subjects; anti-IL-32 staining was used in a second cohort of 132 consecutive untreated chronic HCV patients. Correlations with histological features of steatosis, inflammation, and fibrosis were made. In vitro, endogenous IL-32 in monocytes and in the human hepatoma cell line Huh-7.5 were examined. The effects of IL-32-overexpression and IL-32-silencing on HCV replication were studied using HCV luciferase reporter viruses. There were highly significant positive associations between hepatic IL-32 mRNA expression and liver steatosis, inflammation, fibrosis, smooth muscle actin (SMA) area, and serum alanine aminotransferase (ALT) levels. IL-32 protein expression was positively associated with portal inflammation, SMA area, and ALT. In vitro, IL-1β and TNF-α significantly induced IL-32 expression in human Huh-7.5 cells. Alone, stimulation with interferon alpha (IFN-α) did not induce IL-32 expression in Huh-7.5. However, IFN-α exerted a significant additive effect on TNF-α-induced but not IL-1β-induced IL-32 expression, particularly in CD14+ monocytes. This effect was dependent both on NF-κB and Jak/STAT signaling. Viral infection of Huh-7.5 cells resulted in a significant (11-fold) induction of IL-32 mRNA expression. However, modulation of IL-32 in Huh-7.5 cells by overexpression or silencing did not influence HCV virus replication as determined by luciferase assays.

Conclusion: IL-32 is a novel proinflammatory cytokine involved in HCV-associated liver inflammation/fibrosis. IL-32 is expressed by human hepatocytes and hepatoma cells and its expression is regulated by proinflammatory stimuli.

MeSH terms

  • Adult
  • Biopsy
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / virology
  • Cell Line, Tumor
  • Cohort Studies
  • Female
  • Gene Expression Regulation / drug effects
  • Hepacivirus / physiology
  • Hepatitis C, Chronic / metabolism*
  • Hepatitis C, Chronic / pathology*
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Humans
  • Interferon-alpha / pharmacology
  • Interleukin-1beta / pharmacology
  • Interleukins / metabolism*
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis / metabolism*
  • Liver Cirrhosis / pathology*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Liver Neoplasms / virology
  • Male
  • Middle Aged
  • Retrospective Studies
  • Tumor Necrosis Factor-alpha / pharmacology
  • Virus Replication / physiology

Substances

  • IL32 protein, human
  • Interferon-alpha
  • Interleukin-1beta
  • Interleukins
  • Tumor Necrosis Factor-alpha