Finding a cell-permeable compound to inhibit inflammatory cytokines: Uptake, biotransformation, and anti-cytokine activity of javamide-I/-II esters

Authors: Park, Jae

Submitted to: Life Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/26/2021
Publication Date: 1/5/2022
Citation: Park, J.B. 2022. Finding a cell-permeable compound to inhibit inflammatory cytokines: Uptake, biotransformation, and anti-cytokine activity of javamide-I/-II esters. Life Sciences. 291:120280. https://doi.org/10.1016/j.lfs.2021.120280.
DOI: https://doi.org/10.1016/j.lfs.2021.120280

Interpretive Summary: The aim of this study is to investigate cell transport and anti-cytokine activity of javamide-I/-II esters. Recent studies suggested that javamide-I/-II esters may have strong anti-inflammatory. However, their transport and anti-cytokine activity have not been investigated in monocyte/macrophage-like cells, although these cells are critically involved in chronic/acute inflammation of many human diseases (e.g., diabetes, arthritis, bacterial and viral infection). Therefore, in this paper, the cellular uptakes of javamide-I/-II esters were investigated in THP-1 and human peripheral blood monocytic cells (PBMCs). The data showed that the uptakes of the esters were transported significantly higher than the parent compounds. Also, the uptake was inhibited by peptide transporter-2 (PepT2) blockers, suggesting that a PepT2-like transporter may be involved in the uptake. Additionally, the transported esters were found to be biotransformed into javamide-I/-II in the cells. Furthermore, javamide-I/-II esters was found to significantly inhibit TNF-alpha and MCP-1 in PMBCs, compared to javamide-I/-II. Altogether, javamide-I/-II esters can be transported, biotransformed, and inhibit inflammatory cytokine TNF-alpha and MCP-1 in PBMCs. This study provides new information about javamide-I/-II ester which may be used as potent agents in suppressing major inflammatory cytokine TNF-alpha and MCP-1 in monocyte/macrophage-like cells involved in various stages of inflammation processes.

Technical Abstract: The aim of this study is to investigate cell transport and anti-cytokine activity of javamide-I/-II esters. Several recent studies suggest that javamide-I/-II esters may have strong anti-inflammatory activity. However, there is no information about their transport and anti-cytokine activity in monocyte/macrophage-like cells, although these cells are critically involved in inflammation. Therefore, in this study, the uptake of javamide-I/-II-O-methyl esters was first investigated in THP-1 cells, then their uptake and potential effects on TNF-alpha and MCP-1 was investigated ex vivo using human peripheral blood monocytic cells (PBMCs). In THP-1 cells, the uptake of javamide-I/-II esters was significant with Km of 27µM (P < 0.001). Also, PepT2 substrate/blocker (GlySar and enalapril) inhibited the uptake significantly. Especially, enalapril competitively inhibited the uptake with Ki of 720 µM in the cells. Furthermore, javamide-I/-II esters were biotransformed into javamide-I/-II in THP-1 cells. Because the esters were transported and biotransformed in THP-1 cells, the uptake and biotransformation of the esters were also investigated in PBMCs. The data showed that the esters could be transported and biotransformed in PBMCs, like THP-1 cells. Furthermore, javamide-I/-II esters were found to inhibit inflammatory cytokine TNF-alpha and MCP-1 significantly in PBMCs (P < 0.005). Although both esters significantly inhibited TNF-alpha and MCP-1, javamide-I ester inhibited the cytokines slightly better than javamide-II ester. Therefore, the IC50 values for javamide-I ester on TNF-alpha and MCP-1 inhibition were determined and found to be 1.79 and 0.98 µM, respectively. These data indicate that javamide-I/-II esters, especially javamide-I ester, may be potent compounds to inhibit TNF-alpha and MCP-1 at relatively low concentrations in PBMCs. Altogether, javamide-I/-II-O-methyl esters can be transported, biotransformed and inhibit inflammatory cytokine TNF-alpha and MCP-1 significantly in PBMCs.