Protective effect of interferon on the liver solved – will targeted treatment approaches be available, soon?

Type I interferons are mainly associated with their immunostimulatory, antiviral, and antitumoral effects. However, they also have anti-inflammatory properties. Thus, in patients with a liver inflammation due to a chronic hepatitis-C virus infection, interferon may improve the condition of the liver. This can also be observed when, thanks to treatment, the viral burden is negligible already.

PD (associate professor) Dr Zoe Waibler, head of a temporary research group at the Paul-Ehrlich-Institut (PEI), and co-workers have studied the mechanism which results in this protective effect. For the study not a virus but poly(I:C), an artificial double-stranded RNA which mimics a viral infection, was used. Poly(I:C) was applied to interferon receptor-deficient (IFNAR-deficient) mice and genetically unmodified control mice. In IFNAR-deficient mice, the treatment with poly(I:C) induced a severe acute liver damage with necrosis, while the control animals were protected. Similarly to human liver inflammations, serum levels of the enzyme alanine aminotransferase also increased upon poly(I:C) treatment of IFNAR-deficient mice, while those of the control mice did not. In collaboration with Professor Christian Bogdan, Institute of Clinical Microbiology, Immunology, and Hygiene of the University Hospital of Erlangen, the team of PEI researchers identified certain suppressor cells ("myeloid derived suppressor cells", MDSC) as mediators of protection: Upon type I interferon expression, these cells infiltrate the liver, where they convey the protective effect. The team achieved this by switching off the interferon receptor on individual cell types and studying specific surface markers.

Liver histology of mice after treatment with poly(I:C). While the control mice (WT) are protected by an interferon-mediated effect, mice without the interferon receptor (IFNAR-/-) develop severe liver damage such as liver necroses. Source: PEI

Dr Waibler and co-workers were able to show that these suppressor cells influence the balance between the pro- inflammatory cytokine interleukin-1beta (IL-1beta) and its naturally occurring inhibitor, anti-inflammatory interleukin-1 receptor antagonist (IL-1RA) in the liver: For IFNAR-deficient mice, there was a drastic shift toward inflammatory IL-1beta upon poly(I:C) treatment, while for the control mice, the shift occurred in the direction of the anti-inflammatory IL-1RA.

The fact that IL-1beta and IL-1RA indeed induced the inflammatory or protective effects, respectively, in the liver could be proved by Dr Waibler and co-workers by administrating IL-1RA to IFNAR-deficient mice, which prevented the liver damage induced by poly(I:C). Although interferon could not mediate the protective effect here, due to the missing interferon receptor, the downstream effects, normally mediated by interferon, was restored by the administration of IL-1RA. Likewise, liver functions improved in IFNAR-deficient mice if the inflammatory cytokine IL-1beta was neutralized by adding an anti-IL-1beta antibody.

"Interferons have extremely versatile effects by regulating up to 300 genes, thus bringing about a great variety of effects. Only a minor part of them is responsible for this effect on the liver. Maybe an organ-specific therapy would be possible here", explained Dr Waibler with regard to a potential clinical use of these results. Biotechnologically engineered IL-1RA is used in the treatment of rheumatoid arthritis. In addition, there is a genetically engineered monoclonal antibody directed against IL-1beta, which is used in patients with a particular genetic defect.

The PEI researchers also have an explanation for the fact that the suppressor cells in the control mice infiltrate the liver: Based on experimental results, they assume that interferons switch on a particular chemokine in the liver, which attracts the suppressor cells (MDSC).

"Many immunological processes are not fully understood, yet. With our fundamental research, we contribute to developing approaches to therapies that are effective but at the same time cause as few adverse effects as possible", emphasised Professor Cichutek, president of the Paul-Ehrlich-Institut.

Original publication

DOI:10.1002/hep.26915; unedited version

Conrad E, Resch TK, Gogesch P, Kalinke U, Bechmann I, Bogdan C, Waibler Z (2013): Protection against RNA-induced liver damage by myeloid cells requires type I IFN and IL-1 receptor antagonist. Hepatology [Epub ahead of print].
Online-Abstract