白细胞介素-1β和血小板衍生生长因子-AB 在天然人干扰素 α 介导的抗纤维化中的作用。

The role of interleukin-1beta and platelet-derived growth factor-AB in antifibrosis mediated by native human interferon alpha.

机构信息

Department of Surgery, General County Hospital, Pozega, Croatia.

出版信息

Surgery. 2010 Sep;148(3):490-8. doi: 10.1016/j.surg.2010.01.005. Epub 2010 Feb 21.

DOI:10.1016/j.surg.2010.01.005

PMID:20176391

Abstract

BACKGROUND

Commercial preparations of native human interferon alpha (nHuIFN-alpha) contain several subtypes of interferon-alpha (IFN-alpha) and traces of other cytokines. Recently, we described its antifibrotic potential and showed nHuIFN-alpha to have a greater effect than that of recombinant human IFN-alpha (rHuIFN-alpha). We hypothesized that cooperation between different cytokines in the nHuIFN-alpha preparation is essential for this effect. Considerable concentrations of interleukin-1beta (IL-1beta) and platelet-derived growth factor AB (PDGF-AB) are present in the nHuIFN-alpha preparations.

METHODS

We tested the viability and the expression of procollagen type I messenger RNA (mRNA) in MRC5 fibroblasts treated with interleukin-1 beta (IL-1beta) and/or PDGF-AB, or the corresponding antibodies in combination with rHuIFN-alpha or nHuIFN-alpha.

RESULTS

We showed that neither IL-1beta nor PDGF-AB significantly affect the viability of MRC5 cells. Furthermore, cell viability was not affected when IL-1beta or PDGF-AB were applied along with rHuIFN-alpha, relative to the viability of cells treated with rHuIFN-alpha only. In contrast, both cytokines suppressed the synthesis of procollagen type I mRNA. When coadministered with rHuIFN-alpha, IL-1beta enhanced the suppression induced by rHuIFN-alpha. Conversely, PDGF-AB acted as an antagonist of rHuIFN-alpha and restored partially the synthesis of procollagen type I mRNA. Interestingly, the addition of IL-1beta to the PDGF-AB/rHuIFN-alpha mix not only abolished the antagonistic activity of PDGF-AB but also decreased the synthesis of procollagen type I mRNA beyond the level achieved by IL-1beta/rHuIFN-alpha. Therefore, IL-1beta was able to reverse the activity of PDGF-AB.

CONCLUSION

Our study suggests that IL-1beta is an important component of nHuIFN-alpha preparations, acting directly and indirectly to modulate the action of other components. This study provides insight into these complex cytokine networks, which is necessary for better and safer antifibrotic therapy.

摘要

背景

天然人干扰素-α（nHuIFN-α）的商业制剂含有几种亚型的干扰素-α（IFN-α）和其他细胞因子的痕迹。最近，我们描述了它的抗纤维化潜力，并表明 nHuIFN-α的作用大于重组人干扰素-α（rHuIFN-α）。我们假设 nHuIFN-α制剂中不同细胞因子之间的合作对这种作用至关重要。在 nHuIFN-α制剂中存在相当浓度的白细胞介素-1β（IL-1β）和血小板衍生生长因子 AB（PDGF-AB）。

方法

我们测试了用白细胞介素-1β（IL-1β）和/或 PDGF-AB 处理的 MRC5 成纤维细胞的活力和前胶原 I 信使 RNA（mRNA）的表达，以及 rHuIFN-α或 nHuIFN-α与相应抗体的组合。

结果

我们表明，IL-1β或 PDGF-AB 都不会显著影响 MRC5 细胞的活力。此外，当与 rHuIFN-α一起应用时，IL-1β或 PDGF-AB 不会影响细胞的活力，与仅用 rHuIFN-α处理的细胞的活力相比。相反，这两种细胞因子都抑制了前胶原 I mRNA 的合成。当与 rHuIFN-α一起给予时，IL-1β增强了 rHuIFN-α诱导的抑制作用。相反，PDGF-AB 作为 rHuIFN-α的拮抗剂起作用，并部分恢复前胶原 I mRNA 的合成。有趣的是，将 IL-1β添加到 PDGF-AB/rHuIFN-α混合物中不仅消除了 PDGF-AB 的拮抗活性，而且使前胶原 I mRNA的合成降低到 IL-1β/rHuIFN-α水平以上。因此，IL-1β能够逆转 PDGF-AB 的活性。