Supernatant from Bifidobacterium Differentially Modulates Transduction Signaling Pathways for Biological Functions of Human Dendritic Cells

Abstract

BackgroundProbiotic bacteria have been shown to modulate immune responses and could have therapeutic effects in allergic and inflammatory disorders. However, the signaling pathways engaged by probiotics are poorly understood. We have previously reported that a fermentation product from Bifidobacterium breve C50 (BbC50sn) could induce maturation, high IL-10 production and prolonged survival of DCs via a TLR2 pathway. We therefore studied the roles of mitogen-activated protein kinases (MAPK), glycogen synthase kinase-3 (GSK3) and phosphatidylinositol 3-kinase (PI3K) pathways on biological functions of human monocyte-derived DCs treated with BbC50sn.Methodology/Principal FindingsDCs were differentiated from human monocytes with IL-4 and GM-CSF for 5 days and cultured with BbC50sn, lipopolysaccharide (LPS) or Zymosan, with or without specific inhibitors of p38MAPK (SB203580), ERK (PD98059), PI3K (LY294002) and GSK3 (SB216763). We found that 1) the PI3K pathway was positively involved in the prolonged DC survival induced by BbC50sn, LPS and Zymosan in contrast to p38MAPK and GSK3 which negatively regulated DC survival; 2) p38MAPK and PI3K were positively involved in DC maturation, in contrast to ERK and GSK3 which negatively regulated DC maturation; 3) ERK and PI3K were positively involved in DC-IL-10 production, in contrast to GSK3 that was positively involved in DC-IL-12 production whereas p38MAPK was positively involved in both; 4) BbC50sn induced a PI3K/Akt phosphorylation similar to Zymosan and a p38MAPK phosphorylation similar to LPS.Conclusion/SignificanceWe report for the first time that a fermentation product of a bifidobacteria can differentially activate MAPK, GSK3 and PI3K in order to modulate DC biological functions. These results give new insights on the fine-tuned balance between the maintenance of normal mucosal homeostasis to commensal and probiotic bacteria and the specific inflammatory immune responses to pathogen bacteria.

The cell-envelope proteome of Bifidobacterium longum in an in vitro bile environment

“…They possess key functions in the adaptation to the gastrointestinal environment, as well as in the colonization of host tissues, and in the induction of host downstream responses (Kelly et al, 2005a;Marco et al, 2006). In bifidobacteria, claims have been made regarding, for instance, cell-surface proteinaceous components involved in intestinal adhesion (Mukai et al, 2004), proteinaceous factor(s) in culture supernatant fluids of bifidobacteria which prevent(s) the binding of enterotoxigenic Escherichia coli (Fujiwara et al, 1997), or supernatants of Bifidobacterium breve that can modulate transduction signalling pathways and induce maturation in human dendritic cells (Hoarau et al, 2006(Hoarau et al, , 2008. Also, single molecules responsible for a particular effect have been identified.…”

“…Most of these factors are components localized either in the secreted fraction or in the cell envelope (cell wall or membrane), since this is the part of commensal gut bacteria that is directly exposed to the intestinal epithelium (Candela et al, 2007;Hoarau et al, 2006Hoarau et al, , 2008Ivanov et al, 2006;Marco et al, 2006;Mitsuma et al, 2008). However, currently there are to our knowledge no data about this important subproteome in the genus Bifidobacterium.…”

Extracellular proteins secreted by probiotic bacteria as mediators of effects that promote mucosa–bacteria interactions

“…Extracellular proteins from probiotic bacteria could diffuse through the mucus layer that covers the intestinal mucosa, enabling interaction with epithelial and immune cells. In some cases, the signal is transmitted to the nucleus via different pathways, which generally involve the consecutive action of several kinases, such as mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinase (PI-3K) and glycogen synthase kinase-3 (GSK-3) (Hoarau et al, 2008). The activation of these cascades finally triggers changes in genetic expression and produces physiological changes in the cell.…”

“…Prolonged DC survival was mediated by the PI-3K pathway, DC maturation by the p38 and PI-3K pathways, increase in IL-10 production by the MAPK (p38, ERK) and PI-3K pathways, and finally an increase in IL-12 production was mediated by means of the p38 and GSK-3 pathways (Hoarau et al, 2008). Further research is needed to elucidate the precise role of those proteins.…”

Fermentation products: immunological effects on human and animal models

“…The maturation process of DCs induced by BbC50sn appears to involve nuclear factor-κB (44) and to differentially activate mitogen-activated protein kinase, glycogen synthase kinase-3, and phosphatidylinositol 3-kinase pathways (46). These results give new insights on the fine-tuned balance inducible by specific fermentation products.…”