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Interleukin-32: a new proinflammatory cytokine involved in hepatitis C virus-related liver inflammation and fibrosis.

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.

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  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    Christian Doppler Research Laboratory for Gut Inflammation, Innsbruck Medical University, Innsbruck, Austria.

    , , , , , , , , , ,

    Source

    Hepatology (Baltimore, Md.) 53:6 2011 Jun pg 1819-29

    MeSH

    Adult
    Biopsy
    Carcinoma, Hepatocellular
    Cell Line, Tumor
    Cohort Studies
    Female
    Gene Expression Regulation
    Hepacivirus
    Hepatitis C, Chronic
    Hepatocytes
    Humans
    Interferon-alpha
    Interleukin-1beta
    Interleukins
    Liver
    Liver Cirrhosis
    Liver Neoplasms
    Male
    Middle Aged
    Retrospective Studies
    Tumor Necrosis Factor-alpha
    Virus Replication

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    21381070

    Citation

    Moschen, Alexander R., et al. "Interleukin-32: a New Proinflammatory Cytokine Involved in Hepatitis C Virus-related Liver Inflammation and Fibrosis." Hepatology (Baltimore, Md.), vol. 53, no. 6, 2011, pp. 1819-29.
    Moschen AR, Fritz T, Clouston AD, et al. Interleukin-32: a new proinflammatory cytokine involved in hepatitis C virus-related liver inflammation and fibrosis. Hepatology. 2011;53(6):1819-29.
    Moschen, A. R., Fritz, T., Clouston, A. D., Rebhan, I., Bauhofer, O., Barrie, H. D., ... Tilg, H. (2011). Interleukin-32: a new proinflammatory cytokine involved in hepatitis C virus-related liver inflammation and fibrosis. Hepatology (Baltimore, Md.), 53(6), pp. 1819-29. doi:10.1002/hep.24285.
    Moschen AR, et al. Interleukin-32: a New Proinflammatory Cytokine Involved in Hepatitis C Virus-related Liver Inflammation and Fibrosis. Hepatology. 2011;53(6):1819-29. PubMed PMID: 21381070.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Interleukin-32: a new proinflammatory cytokine involved in hepatitis C virus-related liver inflammation and fibrosis. AU - Moschen,Alexander R, AU - Fritz,Teresa, AU - Clouston,Andrew D, AU - Rebhan,Ilka, AU - Bauhofer,Oliver, AU - Barrie,Helen D, AU - Powell,Elizabeth E, AU - Kim,Soo-Hyun, AU - Dinarello,Charles A, AU - Bartenschlager,Ralf, AU - Jonsson,Julie R, AU - Tilg,Herbert, Y1 - 2011/05/14/ PY - 2010/06/20/received PY - 2011/02/23/accepted PY - 2011/3/8/entrez PY - 2011/3/8/pubmed PY - 2011/8/30/medline SP - 1819 EP - 29 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 53 IS - 6 N2 - UNLABELLED: 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. SN - 1527-3350 UR - https://www.unboundmedicine.com/medline/citation/21381070/Interleukin_32:_a_new_proinflammatory_cytokine_involved_in_hepatitis_C_virus_related_liver_inflammation_and_fibrosis_ L2 - https://doi.org/10.1002/hep.24285 DB - PRIME DP - Unbound Medicine ER -