RESUMO
d-Glycero-ß-d-manno-heptose 1,7-biphosphate (ß-HBP) is a novel microbial-associated molecular pattern that triggers inflammation and thus has the potential to act as an immune modulator in many therapeutic contexts. To better understand the structure-activity relationship of this molecule, we chemically synthesized analogs of ß-HBP and tested their ability to induce canonical TIFA-dependent inflammation in human embryonic kidney cells (HEK 293T) and colonic epithelial cells (HCT 116). Of the analogs tested, only d-glycero-ß-d-manno-heptose 1-phosphate (ß-HMP) induced TIFA-dependent NF-κB activation and cytokine production in a manner similar to ß-HBP. This finding expands the spectrum of metabolites from the Gram-negative ADP-heptose biosynthesis pathway that can function as innate immune agonists and provides a more readily available agonist of the TIFA-dependent inflammatory pathway that can be easily produced by synthetic methods.
Assuntos
Bactérias Gram-Negativas/fisiologia , Heptoses/imunologia , Imunidade Inata , Fatores Imunológicos/imunologia , Inflamação/imunologia , Manose/imunologia , Moléculas com Motivos Associados a Patógenos/imunologia , Fosfatos/imunologia , Piranos/imunologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Células HEK293 , Heptoses/síntese química , Humanos , Imunização , Fatores Imunológicos/síntese química , Inflamação/induzido quimicamente , Manose/síntese química , Fosfatos/síntese química , Piranos/síntese química , Transdução de Sinais , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
d-glycero-ß-d-manno-heptose 1,7-biphosphate (HBP) is an enzymatic intermediate in the biosynthesis of the heptose component of lipopolysaccharide (LPS), and was recently revealed to be a pathogen-associated molecular pattern (PAMP) that allows detection of Gram-negative bacteria by the mammalian immune system. Cellular detection of HBP depends upon its stimulation of a cascade that leads to the phosphorylation and assembly of the TRAF-interacting with forkhead-associated domain protein A (TIFA), which activates the transcription factor NF-κB. In this note, an alternate chemical synthesis of HBP is described and its biological activity is established, providing pure material for further assessing and exploiting the biological activity of this compound.