PASylation of IL-1 receptor antagonist (IL-1Ra) retains IL-1 blockade and extends its duration in mouse urate crystal-induced peritonitis
| Autor: | Rajiv Datar, Carlo Marchetti, Benjamin J Swartzwelter, Charles A. Dinarello, Carl K. Edwards, Uli Binder, Martin Schlapschy, Arne Skerra, Dennis M. de Graaf, Nicholas E. Powers, Alexandra Lerchner |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.drug_class medicine.medical_treatment Immunology lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] Inflammation Pharmacology Peritonitis Peripheral blood mononuclear cell Biochemistry 03 medical and health sciences Mice 0302 clinical medicine All institutes and research themes of the Radboud University Medical Center In vivo Blood plasma medicine Leukocytes Animals Humans Molecular Biology Anakinra Chemistry Antagonist Cell Biology Receptor antagonist Uric Acid Interleukin 1 Receptor Antagonist Protein 030104 developmental biology Cytokine 030220 oncology & carcinogenesis medicine.symptom Biomarkers medicine.drug Interleukin-1 |
| Zdroj: | J Biol Chem Journal of Biological Chemistry, 295, 3, pp. 868-882 Journal of Biological Chemistry, 295, 868-882 |
| ISSN: | 0021-9258 |
| Popis: | Interleukin-1 (IL-1) is a key mediator of inflammation and immunity. Naturally-occurring IL-1 receptor antagonist (IL-1Ra) binds and blocks the IL-1 receptor-1 (IL-1R1), preventing signaling. Anakinra, a recombinant form of IL-1Ra, is used to treat a spectrum of inflammatory diseases. However, anakinra is rapidly cleared from the body and requires daily administration. To create a longer-lasting alternative, PASylated IL-1Ra (PAS–IL-1Ra) has been generated by in-frame fusion of a long, defined-length, N-terminal Pro/Ala/Ser (PAS) random-coil polypeptide with IL-1Ra. Here, we compared the efficacy of two PAS–IL-1Ra molecules, PAS600–IL-1Ra and PAS800–IL-1Ra (carrying 600 and 800 PAS residues, respectively), with that of anakinra in mice. PAS600–IL-1Ra displayed markedly extended blood plasma levels 3 days post-administration, whereas anakinra was undetectable after 24 h. We also studied PAS600–IL-1Ra and PAS800–IL-1Ra for efficacy in monosodium urate (MSU) crystal-induced peritonitis. 5 days post-administration, PAS800–IL-1Ra significantly reduced leukocyte influx and inflammatory markers in MSU-induced peritonitis, whereas equimolar anakinra administered 24 h before MSU challenge was ineffective. The 6-h pretreatment with equimolar anakinra or PAS800–IL-1Ra before MSU challenge similarly reduced inflammatory markers. In cultured A549 lung carcinoma cells, anakinra, PAS600–IL-1Ra, and PAS800-IL-Ra reduced IL-1α–induced IL-6 and IL-8 levels with comparable potency. In human peripheral blood mononuclear cells, these molecules suppressed Candida albicans–induced production of the cancer-promoting cytokine IL-22. Surface plasmon resonance analyses revealed significant binding between PAS–IL-1Ra and IL-1R1, although with a slightly lower affinity than anakinra. These results validate PAS–IL-1Ra as an active IL-1 antagonist with marked in vivo potency and a significantly extended half-life compared with anakinra. |
| Databáze: | OpenAIRE |
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