RESUMEN
C1 esterase inhibitor (C1INH) is an abundant component of blood plasma (the average concentration is 250 mg/L); it is known to be involved in several biological processes, for instance, in the regulation of the coagulation system, adhesion of leukocytes on endothelial cells, and in the regulation of complement and kallikrein cascades. Lately, the role of C1INH in immunomodulation has gained considerable attention. We used an ex vivo whole blood model to examine the influence of C1INH and its mutated variants on the inflammatory cytokines interleukin (IL)-6, tumor necrosis factor-α (TNFα), and IL-1ß. The present study demonstrated for the first time that recombinant C1INH or its Seprin domain can downregulate bacterial endotoxin induced IL-6 release. We also observed that unstructured N-terminal domain of C1INH downregulates the release of IL-1ß and TNFα, but not IL-6. Our results suggest that C1INH may have therapeutic potential for treatment of inflammatory conditions.
Asunto(s)
Proteína Inhibidora del Complemento C1/farmacología , Citocinas/sangre , Modelos Biológicos , Humanos , Interleucina-1beta/sangre , Interleucina-6/sangre , Lipopolisacáridos/farmacología , Masculino , Proteínas Mutantes/farmacología , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Recombinant interferon-ß1b (IFN-ß1b) is an effective remedy against multiple sclerosis and other diseases. However, use of small polypeptide (molecular weight is around 18.5 kDa) is limited due to poor solubility, stability, and short half-life in systemic circulation. To solve this problem, we constructed two variants of PASylated IFN-ß1b, with PAS sequence at C- or N-terminus of IFN-ß1b. The PAS-modified proteins demonstrated 4-fold increase in hydrodynamic volume of the molecule combined with 2-fold increase of in vitro biological activity, as well as advanced stability and solubility of the protein in solution as opposed to unmodified IFN-ß1b. Our results demonstrate that PASylation has a positive impact on stability, solubility, and functional activity of IFN-ß1b and potentially might improve pharmacokinetic properties of the molecule as a therapeutic agent.