Article ; Online: Eculizumab suppresses zymosan-induced release of inflammatory cytokines IL-1α, IL-1β, IFN-γ and IL-2 in autologous serum-substituted PBMC cultures: Relevance to cytokine storm in Covid-19.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
2023 Volume 166, Page(s) 115294
Abstract: Background and objective: Cytokine storm (CS) is a major contributor to the fatal outcome of severe infectious diseases, including Covid-19. Treatment with the complement (C) C5 inhibitor eculizumab was beneficial in end-stage Covid-19, however, the ... ...
| Abstract | Background and objective: Cytokine storm (CS) is a major contributor to the fatal outcome of severe infectious diseases, including Covid-19. Treatment with the complement (C) C5 inhibitor eculizumab was beneficial in end-stage Covid-19, however, the mechanism of this effect is unknown. To clarify this, we analyzed the relationship between C activation and production of pro-inflammatory cytokines in a PBMC model. Methods: Human PBMC with or without 20 % autologous serum was incubated with C3a, C5a, zymosan or zymosan-pre-activated serum (ZAS) for 24 h with or without eculizumab or the C5a receptor antagonist, DF2593A. C activation (sC5b-9) and 9 inflammatory cytokines were measured by ELISA. Results: In serum-free unstimulated PBMC only IL-8 release could be measured during incubation. Addition of C5a increased IL-8 secretion only, ZAS induced both IL-2 and IL-8, while zymosan led to significant production of all cytokines, most abundantly IL-8. In the presence of serum the above effects were greatly enhanced, and the zymosan-induced rises of IL-1α, IL-1β IFN-γ and IL-2 were significantly attenuated by eculizumab but not by DF2593a. Conclusions: These data highlight the complexity of interrelationships between C activation and cytokine secretion under different experimental conditions. The clinically relevant findings include the abundant formation of the chemokine IL-8, which was stimulated by C5a, and the suppression of numerous inflammatory cytokines by eculizumab, which explains its therapeutic efficacy in severe Covid-19. These data strengthen the clinical relevance of the applied PBMC model for drug screening against CS, enabling the separation of complex innate immune cross-talks. |
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| MeSH term(s) | Humans ; Cytokines/pharmacology ; Interleukin-2/pharmacology ; Zymosan/pharmacology ; Leukocytes, Mononuclear ; Cytokine Release Syndrome/drug therapy ; Interleukin-8/pharmacology ; COVID-19 ; Interferon-gamma/pharmacology |
| Chemical Substances | Cytokines ; Interleukin-2 ; Zymosan (9010-72-4) ; eculizumab (A3ULP0F556) ; Interleukin-8 ; Interferon-gamma (82115-62-6) |
| Language | English |
| Publishing date | 2023-08-09 |
| Publishing country | France |
| Document type | Journal Article |
| ZDB-ID | 392415-4 |
| ISSN | 1950-6007 ; 0753-3322 ; 0300-0893 |
| ISSN (online) | 1950-6007 |
| ISSN | 0753-3322 ; 0300-0893 |
| DOI | 10.1016/j.biopha.2023.115294 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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