Interleukin‐32: A new proinflammatory cytokine involved in hepatitis C virus‐related liver inflammation and fibrosis

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. (HEPATOLOGY 2011;)