Immunomodulatory Effects of Propolis on Endothelial Cytokine Release

Propolis is a natural resinous product with a broad spectrum of biological activities, including immunomodulatory and anti-inflammatory effects. Increasing evidence suggests that propolis may influence pathways involved in tissue remodeling and fibrosis; however, comparative studies evaluating different propolis types in endothelial models remain limited. Brain microvascular endothelial cells, as a key component of the blood-brain barrier, constitute a relevant in vitro model for studying anti-inflammatory and neurovascular responses under both physiological and pathological conditions. The aim of this study was to compare the effects of Brazilian green propolis (EEP-BRA) and Polish brown propolis extracts (EEP-PL) on the immunological and fibrotic responses of brain microvascular endothelial cells. Human brain microvascular endothelial cells (hCMEC/D3-BBB) were exposed to propolis extracts (EEP-BRA and EEP-PL) under normoxic and hypoxic conditions to reflect diverse microenvironmental states. The analysis focused on the modulation of release of selected cytokines, including IL-10, IL-4, IL-6, IFN-γ, GM-CSF, TNF-α, IL-2, IL-8, and TGF-β, with particular emphasis on TGF-β as a key regulator of fibrosis. Results: Both propolis extracts significantly modulated cytokine production, although their effects differed depending on the origin of the propolis and oxygen conditions. Under the hypoxia condition followed by IFN-α stimulation, EEP-PL-50 was associated with reduced TNF-α (0.54 vs. 3.61 pg/mL; Hedges g = -6.78; large effect size, p > 0.05) and decreased TGF-β1, IL-8 and TGF-β2/β3. EEP-BRA-50 elicited a distinct profile characterized by increased IL-6 (171.58 vs. 27.63 pg/mL; p < 0.001; g = +6.15) and GM-CSF, while reducing TGF-β1. Both extracts preserved viability > 70% (ISO 10993-5). In conclusion, the results demonstrate that EEP-BRA and EEP-PL exert distinct immunomodulatory effects on brain endothelial cells. These findings highlight the importance of propolis origin in determining its biological activity and support its potential application in modulating inflammation and neurovascular responses.