Native Human IFN- α Is a More Potent Suppressor of HDF Response to Profibrotic Stimuli Than Recombinant Human IFN- α

Abstract

Interferon-α(IFN-α) inhibits fibroblast proliferation, differentiation into myofibroblasts, and extracellular matrix synthesis, which are key events during both normal wound repair and fibrotic lesion formation. Unlike recombinant human IFN-α (rHuIFN-α), a native human IFN-α (nHuIFN-α) consists of several IFN-α subtypes and traces of other cytokines produced by the Sendai virus-stimulated human leukocytes. This study compares the antifibrotic effect of nHuIFN-α and rHuIFN-α in normal human dermal fibroblasts (HDFs). Treatment of HDF culture with nHuIFNA-α markedly affects HDF viability, whereas different rHuIFN-α subtypes show various effects. Two of twelve rHuIFN-α subtypes (IFN-α B2 and IFN-α K) significantly reduce cell viability of HDFs compared with nontreated HDFs. However, nHuIFN-α significantly reduces HDF cell viability in comparison to both nontreated cells and cells treated with rHuIFN-α. The 50% inhibitory concentration (IC₅₀) varied 10-fold between nHuIFN-α and rHuIFN-α (1,103 IU/mL and 10,762 IU/mL, respectively). The impact on procollagen type I mRNA synthesis level is comparable at low doses of IFN (100 and 500 IU/mL), whereas at the dose of 1,000 IU/mL, nHuIFN-α shows higher repression of collagen type I gene than does rHuIFN-α. Both, nHuIFN-α and rHuIFN-α antagonize the effect of exogenous transforming growth factor-β (TGF-β) and interleukin-4 (IL-4) as measured by the α-smooth muscle actin (α -SMA) and procollagen type I mRNA level, but the effect of nHuIFN-α is more pronounced. This study suggests that nHuIFN-α is a more potent suppressor of the HDF response to profibrotic stimuli than rHuIFN-α, probably because of the synergism between different IFN-α subtypes and antifibrotic cytokines and factors.