Santak Goran, Santak Maja, Forcić Dubravko
General County Hospital, Pozega, Croatia.
J Interferon Cytokine Res. 2007 Jun;27(6):481-90. doi: 10.1089/jir.2007.0174.
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.
α干扰素（IFN-α）可抑制成纤维细胞增殖、向肌成纤维细胞分化以及细胞外基质合成，这些都是正常伤口修复和纤维化病变形成过程中的关键事件。与重组人α干扰素（rHuIFN-α）不同，天然人α干扰素（nHuIFN-α）由几种IFN-α亚型以及仙台病毒刺激的人白细胞产生的其他细胞因子痕量组成。本研究比较了nHuIFN-α和rHuIFN-α对正常人皮肤成纤维细胞（HDF）的抗纤维化作用。用nHuIFNA-α处理HDF培养物会显著影响HDF活力，而不同的rHuIFN-α亚型表现出不同的作用。与未处理的HDF相比，12种rHuIFN-α亚型中的两种（IFN-α B2和IFN-α K）显著降低了HDF的细胞活力。然而，与未处理的细胞和用rHuIFN-α处理的细胞相比，nHuIFN-α显著降低了HDF细胞活力。nHuIFN-α和rHuIFN-α之间的50%抑制浓度（IC50）相差10倍（分别为1103 IU/mL和10762 IU/mL）。在低剂量IFN（100和500 IU/mL）时，对I型前胶原mRNA合成水平的影响相当，而在1000 IU/mL剂量时，nHuIFN-α对I型胶原基因的抑制作用比rHuIFN-α更高。通过α平滑肌肌动蛋白（α -SMA）和I型前胶原mRNA水平测定，nHuIFN-α和rHuIFN-α均拮抗外源性转化生长因子-β（TGF-β）和白细胞介素-4（IL-4）的作用，但nHuIFN-α的作用更明显。本研究表明，nHuIFN-α比rHuIFN-α更有效地抑制HDF对促纤维化刺激的反应，这可能是由于不同IFN-α亚型与抗纤维化细胞因子和因子之间的协同作用。
