Methyl 2-[3-(4-hydroxyphenyl)prop-2-enoylamino]-3-phenylpropanoate is a potent cell-permeable anti-cytokine compound to inhibit inflammatory cytokines in monocyte/macrophage-like cells

Authors: Park, Jae

Submitted to: Journal of Pharmacology and Experimental Therapeutics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/2/2023
Publication Date: 1/1/2024
Citation: Park, J.B. 2024. Methyl 2-[3-(4-hydroxyphenyl)prop-2-enoylamino]-3-phenylpropanoate is a potent cell-permeable anti-cytokine compound to inhibit inflammatory cytokines in monocyte/macrophage-like cells. Journal of Pharmacology and Experimental Therapeutics. 388(1):181-189. https://doi.org/10.1124/jpet.123.001830.
DOI: https://doi.org/10.1124/jpet.123.001830

Interpretive Summary: Worldwide, bacterial/viral infectious diseases are a leading cause of human death. During the infection, inflammatory cytokines such as TNF-alpha, IL-1beta, IL-6 and IL-8 are significantly up-regulated then, followed by sepsis. The severity of sepsis is frequently augmented due to over-activation of cytokine surge called “the cytokine storm”. Therefore, especially in the nutritional sector, there are on-going research efforts to find phytochemicals able to inhibit inflammatory cytokines. Caffedymine-type phenolic amides (CTPAs) are phenylalanine/tyrosine-conjugated phenolic amides found in plant sources such as Coffea sp., Allium sativa, Cannabis sp., Capsicum sp. and Lycium sp. Our study shows that MHPAP (an ester of CTPAs) can inhibit inflammatory cytokines (TNF-alpha, IL-1beta, IL-6, and IL-8) significantly in THP-1 cells. Also, the data suggest that MHPAP can inhibit NF-kB p65 phosphorylation significantly in the cells. Furthermore, the data show that MHPAP can inhibit the inflammatory cytokines significantly in not only THP-1 but also human peripheral blood monocytes cells. As potential health benefits of phytochemicals continue to be recognized, this study provides new information about MHPAP which can be a potent compound to inhibit inflammatory cytokines in monocyte/macrophage-like cells.

Technical Abstract: Cytokines are signaling molecules critically involved in several stages of inflammation process during bacterial and viral infections Therefore, there are relentless efforts to find a potent compound to inhibit inflammatory cytokines. Methyl 2-[3-(4-hydroxyphenyl)prop-2-enoylamino]-3-phenylpropanoate (MHPAP) is one of caffedymine-type phenolic amide esters which were reported to be transported inside monocyte/macrophage-like cells. However, there is no information about potential effects of MHPAP on inflammatory cytokines such as IL-6, IL-1beta, IL-8 and TNF-alpha. Therefore, the effects of MHPAP on these inflammatory cytokines were investigated in monocyte/macrophage-like cells (THP-1 and human peripheral blood mononuclear cells (PBMCs)). In THP-1 cells, MHPAP significantly inhibited IL-6, IL-1beta, IL-8 and TNF-alpha (P < 0.05). Also, MHPAP was found to significantly inhibit NF-kB p65 phosphorylation in THP-1 cells (P < 0.05), despite little effects on c-FOS, ATF-2 and JUN phosphorylations in the cells. In fact, the inhibition of NF-kB p65 phosphorylation was further supported by in silico analysis, demonstrating that MHPAP can bind to IKK complexes better than a known IKK inhibitor, (E)-2-fluoro-4'-methoxystilbene. These data suggest that MHPAP may inhibit the cytokines via suppressing NF-kB pathway. Due to the strong inhibition by MHPAP in THP-1 cells, potential effects of MHPAP on inflammatory cytokines (IL-6, IL-1beta, IL-8 and TNF-alpha) were also investigated in PBMCs. MHPAP was found to inhibit IL-6, IL-1beta, IL-8 and TNF-alpha significantly in PBMCs (P < 0.05), better than in THP-1. Especially, MHPAP inhibited IL-6 with IC50 of 0.85 µM, better than TNF-alpha, IL-1beta and IL-8. Altogether, MHPAP may be a potent cell-permeable anti-cytokine compound which can be used as a potent candidate molecule to inhibit inflammatory cytokines, especially IL-6, in monocyte/macrophage-like cells.