BPAF-induced inflammatory response via estrogen signaling: insights from in vivo and in vitro evidence

This study investigated the effects of BPAF on the indicators related to inflammatory response and explored the roles of G protein estrogen membrane receptor 1 (GPER1) in this process. The results found that BPAF promoted the secretion of pro-inflammatory cytokines such as IL-1β, IL-8 and TNF-α, increased the protein expression of IL-1β and IL-6, and upregulated the relative mRNA levels of inflammatory related genes in Jurkat cells. In vivo SD rat experiments also found that BPAF exposure significantly upregulated the levels of serum inflammatory cytokines, elevated the relative mRNA expression of inflammatory related genes in immune organs, and induced damage of immune organs. In addition, BPAF upregulated the protein expression of GPER1 and elevated the relative mRNA expression of PI3K, AKT and MAPKs genes in Jurkat cells. GPER1 inhibitor G15 suppressed the upregulation of MAPK3, PI3K and AKT genes and concurrently inhibited the relative mRNA expression of inflammatory response genes, indicating that GPER1 activates the PI3K/AKT and MAPK signaling pathways and that this activation contributes to BPAF-induced inflammatory response at the transcriptional level. Molecular docking further confirmed that BPAF directly binds to GPER1. These results suggest that BPAF induces immunotoxicity by activating GPER1-mediated PI3K/AKT and MAPK signaling pathways.