Therapeutic area
Interferon
Type I interferons (IFNs) are a group of proteins with anti-virus activity, secreted extracellularly from vertebrate animal cells when they are stimulated by virus infections or antigenic stimulants. IFNs have been shown to have, in addition to their antiviral activity, other diversified physiological properties such as cell growth-inhibitory and immunomodulatory activities. Type I IFNs include a multigene family of different IFN alpha subtypes and a single IFN beta. All type I IFNs are structurally related and share the same IFN receptor. After binding to the receptor, IFNs activate the Jak-Stat (signal transducer and activator of transcription) signaling pathway. Signal transduction from the receptor to the nucleus is mediated by receptor-associated protein tyrosine kinases, Jak1 and Tyk2, which phosphorylate and activate mainly Stat1, Stat2 and Stat3 proteins. Stat1 and Stat2 dimerize, translocate into the nucleus and together with interferon regulatory factor-9 (IRF9) form ISGF3 transcription factor complex, which binds to the promoter elements of IFN stimulated genes. Also, IFN-activated Stat1 and Stat3 can form homodimers or Stat1-Stat3 heterodimers.
Hepatitis C virus (HCV) can evade the interferon system, an ability that may favor both the chronicity of the infection and the frequent resistance to IFN alpha therapy. The mechanisms by which HCV escapes to IFN alpha and induces liver injury remain poorly understood. IFN alpha combined with ribavirin has been the treatment of choice for chronic hepatitis C. The efficacy of this treatment is about 90% in patients infected by HCV genotypes 2 or 3. However, in patients infected by HCV genotype 1, which accounts for about 80% of cases in the Asia and western countries, the response to treatment is only in the range of 40 to 50% of patients. Several factors, including both host and viral, have been proposed to explain the lack of response of HCV infection to IFN alpha therapy. It has been reported that HCV proteins hampers IFN alpha response by interfering with IFN alpha signal transduction pathway and consequently with their antiviral effects.
Our group has previously observed that in patients with chronic hepatitis C there is a sharp decrease in the Stat3 activation level, which is inversely related with the viral load as well as other damage hepatic parameters as transaminases levels. We have also observed a clear impairment of IFN alpha-induced activation of Stat1, Stat2 and Stat3 in hepatic cells carrying HCV genomic replicon, indicating that HCV replication blocks IFN alpha signalling pathway.
It is well known that Stats can be activated by IL-6 family cytokines as interleukin-6 (IL-6), oncostatin M (OSM) or cardiotrophin 1 (CT-1), among others. The IL-6 family cytokines use the common receptor subunit gp 130 for the activation of signal transduction pathway, which involves the activation of gp 130 associated kinases and phophorilation of Stat3 and Stat1. It has been reported that Stat3 activation by IL-6 family cytokines provides hepatoprotection in various models of liver injury.
We have found that IFN alpha in combination with IL-6 family cytokines, and particularly OSM, is able to produce a higher antiviral effect, as compare to IFN alpha or OSM administrated alone, in the HCV genomic replication system. Also, we have observed that IFN alpha plus OSM is able to break the blockage of IFN alpha signal transduction pathway in hepatic HCV infected cells, and consequently, yields higher expression of genes with antiviral and immunomodulatory activities.
Therefore, the administration of IFN alpha in combination with OSM may represent a therapeutic advantage in patients with chronic hepatitis C. Consequently, our main interest is the identification of up- and down-regulated genes stimulated by IFN-alpha in combination with OSM, which may suggest biological pathways relevant in the antiviral response. The identification of these gene profiles may contribute to better define the potential advantages of using IFN-alpha in combination with OSM in the treatment of chronic hepatitis C.
