Role of interleukin-30 as a modulator of transcription signaling in liver injury

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  • Potential conflict of interest: Nothing to report.

To the Editor:

Dr. Dibra and colleagues1 demonstrated that interleukin (IL)-30 reduced hepatotoxicity through the downregulation of interferon (IFN)-γ in a mouse model of T cell-mediated hepatitis. These findings suggest that IL-30 therapy may represent a promising strategy to minimize liver damage in several clinical settings. However, there is conflicting evidence that IL-30 may enhance liver injury through the suppression of IL-6/glycoprotein (gp) 130/signal transducer and activator of transcription (STAT) 3 signaling. In a study of hepatocyte-specific gp130 knockout mice, IL-6/gp130/STAT3 signaling ameliorated liver injury in concanavalin A-induced hepatitis.2 Also, in a study of macrophage/neutrophil-specific gp130 knockout mice, deletion of gp130 significantly decreased release of IL-6 from immune cells and was associated with more severe liver injury of concanavalin A hepatitis.3 In IL-10–deficient mice, additional deletion of IL-6 or STAT3 resulted in hepatic steatosis and the elevation of serum alanine aminotransferase.4 Thus, activation of IL-6/gp130/STAT3 signaling plays an important role in protecting against liver injury, whereas IL-30 inhibited interaction of IL-6 with gp130 and decreased IL-6–mediated production of IL-10 in a dose-dependent manner.5 Does IL-30 suppress the production of IFN-γ at the cellular or molecular level? IL-27 is composed of IL-27p28 (IL-30), Epstein-Barr virus-induced gene 3 (EBI3), and an IL-6-like protein. Each subunit of IL-27 may be secreted independently and may share the T cell cytokine receptor (TCCR). IL-27/EBI3-deficient mice were protected from concanavalin A-induced liver injury through the downregulation of IFN-γ.6 IL-30 may function as an EBI3 antagonist by competing binding to TCCR, wherein overall effect of IL-30 in liver injury may be dependent on the balance between IL-30 and IL-27 or EBI3.

Tetsuji Fujita M.D.*, * Department of Surgery, Jikei University School of Medicine, Tokyo, Japan.

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