Document Type
Article
Publication Date
8-11-2020
Abstract
Interleukin-10 (IL-10) is an immunoregulatory cytokine that plays a pivotal role in modulating inflammation. IL-10 has inhibitory effects on proinflammatory cytokine production and function in vitro and in vivo; as such, IL-10 is viewed as a potential treatment for various inflammatory diseases. However, a significant drawback of using IL-10 in clinical application is the fact that the biologically active form of IL-10 is an unstable homodimer, which has a short half-life and is easily degraded in vivo. Consequently, IL-10 therapy using recombinant native IL-10 has had only limited success in the treatment of human disease. To improve the therapeutic potential of IL-10, we have generated a novel form of IL-10, which consists of two IL-10 monomer subunits linked in a head to tail fashion by a flexible linker. We show that the linker length per se did not affect the expression and biological activity of the stable IL-10 molecule, which was more active than natural IL-10, both in vitro and in vivo. We confirmed that the new form of IL-10 had a much-improved temperature- and pH-dependent biological stability compared to natural IL-10. The IL-10 dimer protein binds to the IL-10 receptor similarly to the natural IL-10 protein, as shown by antibody blocking and through the genetic modifications of one monomer in the IL-10 dimer specifically at the IL-10 receptor binding site. Finally, we showed that stable IL-10 is more effective at suppressing LPS-induced-inflammation in vivo compared to the natural IL-10. In conclusion, we have developed a new stable dimer version of the IL-10 protein with improved stability and efficacy to suppress inflammation. We propose that this novel stable IL-10 dimer could serve as the basis for the development of targeted anti-inflammatory drugs.
Recommended Citation
Minshawi, Faisal; Lanvermann, Sebastian; McKenzie, Edward; Jeffery, Rebecca; Couper, Kevin; Papoutsopoulou, Stamatia; Roers, Axel; and Muller, Werner, "The Generation of an Engineered Interleukin-10 Protein With Improved Stability and Biological Function" (2020). Center for Translational Medicine Faculty Papers. Paper 73.
https://jdc.jefferson.edu/transmedfp/73
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
32849644
Language
English
Comments
This article is the author’s final published version in Frontiers in Immunology, Volume 11, August 2020, Article number 1794.
The published version is available at https://doi.org/10.3389/fimmu.2020.01794. Copyright © Minshawi et al.