Abstract:
III interferons signals through a combination of two heterodimer receptors (IFN-λRα and IL-10Rβ) and activates the anti-viral pathways like ISRE, GAS driven transcriptions or STAT independent actions. All type III IFNs were preferred over type I IFNs as a candidate for antiviral regimen since their discovery, because of the selective expression of their private receptor chain i.e. IFN-λRα, which lessens the side effects during their therapies. We investigated the expression pattern of IFN-λRα in macrophages, their precursor cells i.e. monocytes, HEK293 and HepG2 cells through various techniques and showed that the expression of IFN-λRα neither depends on the strength of its signal peptide, nor on the balance maintained by the expression of its splice variants, rather on the epigenetics (transcription factors) involved. We furthermore investigated the SNPs involved in the TFBS of those TFs and found that NFYA is the most important of all TFs predicted and literature shows that SNPs involved in its TFBS affect the outcome of IFN-α therapy. We further studied the behavior of IFN-λ4 protein in macrophages and HepG2 cells and elucidated its ability to activate ISGs comparable to IFN-λ3 and identified the receptor complex in its mode of action. Our study shows that although SNPs identified in IL-28B are found to be an important factor in predicting the outcomes of IFN-α therapies, but we cannot neglect the importance of the naturally occurring SNPs in its receptor too, which can also result in resistant IFN-α treatments for HCV patients, moreover controversies regarding the natural expression of IFN-λ4 and pessimistic effects on HCV treatment should be reconsidered as we have shown its potent antiviral behavior in vitro.
