20.500.12556/RUL-138682 Nucleotide-binding oligomerization domain 1/Toll-like receptor 4 co-engagement promotes non-specific immune response against K562 cancer cells Nucleotide-binding oligomerization domain 1 (NOD1) receptor and Toll-like receptor 4 (TLR4) belong to the family of pattern recognition receptors. Interactions between these receptors profoundly shape the innate immune responses. We previously demonstrated that co-stimulation of peripheral blood mononuclear cells (PBMCs) with D-glutamyl-meso-diaminopimelic acid (iE-DAP)-based NOD1 agonists and lipopolysaccharide (LPS), a TLR4 agonist, synergistically increased the cytokine production. Herein, we postulate that stimulation of NOD1 alone or a combined stimulation of NOD1 and TLR4 could also strengthen PBMC-mediated cytotoxicity against cancer cells. Initially, an in-house library of iE-DAP analogs was screened for NOD1 agonist activity to establish their potency in HEK-Blue NOD1 cells. Next, we showed that our most potent NOD1 agonist SZZ-38 markedly enhanced the LPS-induced cytokine secretion from PBMCs, in addition to PBMC- and natural killer (NK) cell-mediated killing of K562 cancer cells. Activation marker analysis revealed that the frequencies of CD69$^+$, CD107a$^+$, and IFN-γ$^+$ NK cells are significantly upregulated following NOD1/TLR4 co-stimulation. Of note, SZZ-38 also enhanced the IFN-γ-induced PBMC cytotoxicity. Overall, our findings provide further insight into how co-engagement of two pathways boosts the non-specific immune response and attest to the importance of such interplay between NOD1 and TLR4. NOD1 agonist TLR4 agonist LPS synergy cytolytic activity PBMC NK cells K562 agonist NOD1 agonist TLR4 sinergija citolitična aktivnost celice NK farmacevtska kemija imunski odziv true false true Angleški jezik Slovenski jezik Članek v reviji 2022-08-09 11:50:49 2022-08-09 11:50:56 2025-08-08 13:21:22 0000-00-00 00:00:00 2022 0 0 12 str. art. 920928 Vol. 13 2022 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.4:54:616-097 1663-9812 10.3389/fphar.2022.920928 117623555 fphar-13-920928.pdf fphar-13-920928.pdf 1 270E77E16A76F419EF5C565A199A0C68 233a02ee2037c12f19cc25885335c2f1019137f21b1cd843a15945ad045ac393 0d8ac30e-17c9-11ed-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=159081 https://www.frontiersin.org/articles/10.3389/fphar.2022.920928/full 1 7a56fb05-17c8-11ed-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=159080 Fakulteta za farmacijo 0 0 0