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SYNERGISTIC ACTIVATION OF GENE TRANSCRIPTION ENCODING TYPE I INTERFERONS AND CYTOKINES IN MACROPHAGES AND DENDRITIC CELLS BY THE COMBINATIONS OF TWO PRR-AGONISTS


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Abstract

Pattern recognition receptors (PRR) detecting pathogen-associated molecular patterns are necessary for both innate and adaptive immune responses [1]. PRR-agonist binding to its receptors on host cells activates their defense program against infections and tumors. Stimulation of innate immunity cells by combinations of two or more PRR-agonists induces synergistic defensive response. We examined the efficacy of innate defense reactions in dendritic cells and macrophages activated by paired combinations of TLR4, TLR9 and NOD2 agonists, localized on the cell membrane, and in endosome and cytosol, respectively. All the tested combinations of agonists, namely, TLR4 + TLR9, TLR4 + NOD2, and TLR9 + NOD2, induced synergistic production of substances which determine anti-infective and anti-cancer defense efficacy. Synergistic responses depended on the concentration of PRR-agonists. We report in this paper that macrophages and dendritic cells’ synergistic responses induced by the paired combinations of TLR4, TLR9 and NOD2 are based on synergistic transcription of type I interferon (INFβ) and pro-inflammatory cytokine (TNFα and IL6) genes. These results show a cooperation between several PRR-pathways at the level of gene transcription.


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