Nucleotide-Binding oligomerization domain 1/Toll-like receptor 4 co-engagement promotes non-specific immune response against K562 cancer cells

Samo Guzelj (Author), Žiga Jakopin (Author)

Abstract

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.

Keywords

NOD1 agonist;TLR4 agonist;LPS;synergy;cytolytic activity;PBMC;NK cells;K562;

Data

Language:	English
Year of publishing:	2022
Typology:	1.01 - Original Scientific Article
Organization:	UL FFA - Faculty of Pharmacy
UDC:	615.4:54:616-097
COBISS:	117623555
ISSN:	1663-9812
Views:	177
Downloads:	44
Average score:	0 (0 votes)
Metadata:

Other data

Secondary language:	Slovenian
Secondary keywords:	agonist NOD1;agonist TLR4;sinergija;citolitična aktivnost;celice NK;Farmacevtska kemija;Imunski odziv;
Type (COBISS):	Article
Pages:	12 str.
Volume:	ǂVol. ǂ13
Issue:	art. 920928
Chronology:	2022
DOI:	10.3389/fphar.2022.920928
ID:	16146524