Roles of intracellular calcium and NF-kappaB in the Bacillus Calmette-Guérin-induced secretion of interleukin-8 from human monocytes.
Interleukin (IL)-8 secretion contributes to the early host response against mycobacterial infection by increasing local inflammation and recruiting professional phagocytes. Because the mechanisms through which Mycobacterium bovis Calmette-Guérin (BCG) induces IL-8 secretion are unknown, the aim of the present study was to characterize the nature of IL-8 production induced by BCG in human monocytes. In this study, we found that the induction of IL-8 synthesis was dose- and time-dependent after stimulation with BCG. This IL-8 secretion was not attributed to LPS contamination or the presence of TNF-alpha. We also determined that BCG-induced IL-8 secretion occurs through a mechanism that requires intracellular calcium and likely involves a calmodulin-sensitive step. Interestingly, BCG-induced secretion of IL-8 from human monocytes resulted from transcriptional up-regulation of the IL-8 gene. Moreover, we present evidence that BCG activates nuclear translocation of the transcription factor NF-kappaB, since pretreatment of monocytes with sulfasalazine, a inhibitor of NF-kappaB activity, blocked the ability of BCG to induce IL-8 secretion in a dose-dependent manner, producing 92.5% inhibition at a concentration of 2 mM. These results were further supported by the fact that treatment of cells with curcumin, another well-described inhibitor of NF-kappaB activity with a different mechanism of action, significantly diminished the effect of BCG on IL-8 secretion. Together, these studies are the first to demonstrate that BCG-induced IL-8 secretion by human monocytes appears to be mediated by intracellular Ca(2+) and is NF-kappaB-dependent and at the same time suggest that production of IL-8 in response to M. bovis BCG can contribute to the initial local and systemic inflammatory response in human tuberculosis.
Méndez-Samperio
P
P
Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, IPN, Carpio y Plan de Ayala, México, D.F, 11340, México.
Palma
J
J
Vázquez
A
A
D002118:Calcium / Q000276:immunology*; D002147:Calmodulin / Q000276:immunology; D002478:Cells, Cultured; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007424:Intracellular Fluid / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D009163:Mycobacterium bovis / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology*; D014158:Transcription, Genetic; D015854:Up-Regulation
D002147:Calmodulin; D016209:Interleukin-8; D016328:NF-kappa B; D002118:Calcium