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

Guzelj, Samo (avtor), Jakopin, Žiga (avtor)

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.

• Jezik: Angleški jezik
• Ključne besede: NOD1 agonist, TLR4 agonist, LPS, synergy, cytolytic activity, PBMC, NK cells, K562
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2022
• Št. strani: 12 str.
• Številčenje: Vol. 13, art. 920928
• PID: 20.500.12556/RUL-138682-14c3a078-d0fe-62c5-3f1a-393bbe4eb580
• UDK: 615.4:54:616-097
• ISSN pri članku: 1663-9812
• DOI: 10.3389/fphar.2022.920928
• COBISS.SI-ID: 117623555
• Datum objave v RUL: 09.08.2022

Gradivo je del revije

• Naslov: Frontiers in pharmacology
• Skrajšan naslov: Front Pharmacol
• Založnik: Frontiers Media
• ISSN: 1663-9812
• COBISS.SI-ID: 29551833

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: agonist NOD1, agonist TLR4, sinergija, citolitična aktivnost, celice NK, farmacevtska kemija, imunski odziv