Evidence for correlation between the intensities of adjuvant effects and NOD2 activation by monomeric, dimeric and lipophylic derivatives of N-acetylglucosaminyl-N-acetylmuramyl peptides.
Adjuvanticity of a series of peptidoglycan fragments-known as muramyl peptides-and their lipophylic derivatives was examined and compared with the ability of these compounds to activate NF-kB pathway through NOD2. The adjuvant activity of di, tetrasaccharide peptides and stearoyl containing derivatives has at least two peaks in dose-response curves and the greater of them correlates with respective dose-response data for NF-kB stimulation through NOD2. Introduction of stearoyl moiety, with the aim of improving muramyl peptide interaction with the cell membrane and subsequent intracellular delivery, influenced the corresponding activities in vitro, but did not correlate with improved effects in vivo experiments. IgG subtypes tests indicate that muramyl peptides preferentially stimulate IgG(1) production, whereas the tetrasaccharide containing muramyl peptide additionally induces production of IgG(2b) subclasses. On the whole, comparison of the adjuvanticity in vivo and the NOD2 activation in vitro revealed a clear correlation between the two responses. These findings confirm the view that NOD2 pathway activation should account, at least in part, for the adjuvant effects of these compounds.
Meshcheryakova
Elena
E
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya 16/10, 117997 Moscow, Russia. eam@mail.ibch.ru
Makarov
Evgenii
E
Philpott
Dana
D
Andronova
Tat'yana
T
Ivanov
Vadim
V
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D019281:Dimerization; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism*; D010457:Peptidoglycan / Q000494:pharmacology*
D000276:Adjuvants, Immunologic; D016328:NF-kappa B; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D010457:Peptidoglycan