RESUMEN
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.
Asunto(s)
Bacterias Gramnegativas/fisiología , Heptosas/inmunología , Inmunidad Innata , Factores Inmunológicos/inmunología , Inflamación/inmunología , Manosa/inmunología , Moléculas de Patrón Molecular Asociado a Patógenos/inmunología , Fosfatos/inmunología , Piranos/inmunología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Células HEK293 , Heptosas/síntesis química , Humanos , Inmunización , Factores Inmunológicos/síntesis química , Inflamación/inducido químicamente , Manosa/síntesis química , Fosfatos/síntesis química , Piranos/síntesis química , Transducción de Señal , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
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.