Caspofungin suppresses zymosan-induced cytokine and chemokine release in THP-1 cells: Possible involvement of the spleen tyrosine kinase pathway.
Transl Res. 2020 Jul 17;:
Authors: Itoh K, Shigemi H, Chihara K, Sada K, Yamauchi T, Iwasaki H
Systemic inflammatory response syndrome and sepsis are considered to contribute to hypercytokinemia in both patients with severe infection and immunocompromised condition. Past research has demonstrated that antibiotics and antifungals not only have antimicrobial efficacy but also affect the immune system. We previously examined whether immune cells were modulated by antibiotics such as tetracyclines or macrolides. The modulation of lipopolysaccharide-stimulated cells by those agents was elucidated. However, few reports about the modulation of the immune system by antifungal agents were found. In this study, the production of pro-inflammatory cytokines and chemokines and signaling pathways involved were investigated in zymosan-activated THP-1 cells. The effects were examined using antifungal agents such as echinocandin including caspofungin (CAS) and micafungin. Pro-inflammatory cytokine and chemokine levels were determined using enzyme linked immunosorbent assay (ELISA). Protein phosphorylation was evaluated by western blot analysis. CAS significantly decreased zymosan-induced pro-inflammatory cytokine and chemokine release in THP-1 cells. CAS (30 µg/mL) also downregulated tumor necrosis factor alpha levels, as shown by ELISA. In western blot analysis, inhibitor of nuclear factor-kappa-B alpha, p38, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and nuclear factor of activated T-cells phosphorylation and activation of caspase-1 and spleen tyrosine kinase (Syk) were downregulated. The major underlying mechanism of pro-inflammatory cytokine and chemokine suppression by CAS is to inhibit activation of Syk and its downstream signaling molecules. Based on the results, it can be concluded that CAS activity possibly involves Syk signaling pathways and has potential to prevent hypercytokinemia in fungal sepsis.
PMID: 32687976 [PubMed - as supplied by publisher]