Linking propolis chemical composition and geographical origin to immunomodulatory effects in human immune cells

ETHNOPHARMACOLOGICAL RELEVANCE: Propolis is a resinous bee product traditionally used for its anti-inflammatory activity; however, its chemical complexity limits standardization and ethnopharmacological validation. This study integrated chemical profiling with functional immune assays to identify compounds underlying its anti-inflammatory effects. METHODS: -transformed HPLC fingerprints and IL-1β data were analysed using multivariate methods, including partial least squares (PLS) regression, selectivity ratios (SRs), forward stepwise selection (FSS), and corrected Akaike's Information Criterion (AICc). Additional cytokines were measured using a mesoscale multiplex immunoassay. RESULTS: -transformation, the chrysin-associated peak emerged as the most consistently supported candidate for independent, compound-specific IL-1β suppression. Multiplex cytokine profiling further demonstrated that propolis decreased IL-1β, IL-10, and IFN-γ while increasing IL-4, IL-6, and TNF-α, indicating a multifaceted immunomodulatory effect, including a Th1-to-Th2 shift. CONCLUSION: Propolis demonstrated anti-inflammatory and immunomodulatory properties supporting its traditional use. Geographic variation in chemistry was associated with differences in IL-1β suppression. Chemometric analysis identified overall composition and the chrysin-associated signal as the most consistently supported putative candidate for compound-specific anti-inflammatory activity, while cytokine profiling further indicated that propolis acts as a complex immunomodulator rather than a broad immunosuppressant.