title: Native human IFN-alpha is a more potent suppressor of HDF response to profibrotic stimuli than recombinant human IFN-alpha.
abstract: Interferon-alpha(IFN-alpha) 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-alpha (rHuIFN-alpha), a native human IFN-alpha (nHuIFN-alpha) consists of several IFN-alpha subtypes and traces of other cytokines produced by the Sendai virus-stimulated human leukocytes. This study compares the antifibrotic effect of nHuIFN-alpha and rHuIFN-alpha in normal human dermal fibroblasts (HDFs). Treatment of HDF culture with nHuIFNA-alpha markedly affects HDF viability, whereas different rHuIFN-alpha subtypes show various effects. Two of twelve rHuIFN-alpha subtypes (IFN-alpha B2 and IFN-alpha K) significantly reduce cell viability of HDFs compared with nontreated HDFs. However, nHuIFN-alpha significantly reduces HDF cell viability in comparison to both nontreated cells and cells treated with rHuIFN-alpha. The 50% inhibitory concentration (IC(50)) varied 10-fold between nHuIFN-alpha and rHuIFN-alpha (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-alpha shows higher repression of collagen type I gene than does rHuIFN-alpha. Both, nHuIFN-alpha and rHuIFN-alpha antagonize the effect of exogenous transforming growth factor-beta (TGF-beta) and interleukin-4 (IL-4) as measured by the alpha-smooth muscle actin (alpha -SMA) and procollagen type I mRNA level, but the effect of nHuIFN-alpha is more pronounced. This study suggests that nHuIFN-alpha is a more potent suppressor of the HDF response to profibrotic stimuli than rHuIFN-alpha, probably because of the synergism between different IFN-alpha subtypes and antifibrotic cytokines and factors.
authors.affiliation: General County Hospital, Pozega, Croatia.
authors.forename: Goran
authors.initials: G
authors.lastname: Santak
authors.forename: Maja
authors.initials: M
authors.lastname: Santak
authors.forename: Dubravko
authors.initials: D
authors.lastname: Forcić
mesh_terms: D000199:Actins / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics; D005347:Fibroblasts; D005786:Gene Expression Regulation; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D015847:Interleukin-4 / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins; D012867:Skin / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors
chemical_list: D000199:Actins; D024042:Collagen Type I; D007370:Interferon Type I; D016898:Interferon-alpha; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D015847:Interleukin-4