Stimulation of Interleukin-10 Production by Acidic β-Lactoglobulin-Derived Peptides Hydrolyzed withLactobacillus paracaseiNCC2461 Peptidases

Abstract

We have previously demonstrated that Lactobacillus paracasei NCC2461 may help to prevent cow's milk allergy in mice by inducing oral tolerance to ␤-lactoglobulin (BLG). To investigate the mechanisms involved in this beneficial effect, we examined the possibility that L. paracasei induces tolerance by hydrolyzing BLGderived peptides and liberating peptides that stimulate interleukin-10 (IL-10) production. L. paracasei peptidases have been shown to hydrolyze tryptic-chymotryptic peptides from BLG, releasing numerous small peptides with immunomodulating properties. We have now shown that acidic tryptic-chymotryptic peptides stimulate splenocyte proliferation and gamma interferon (IFN-␥) production in vitro. Hydrolysis of these peptides with L. paracasei peptidases repressed the lymphocyte stimulation, up-regulated IL-10 production, and down-regulated IFN-␥ and IL-4 secretion. L. paracasei NCC2461 may therefore induce oral tolerance to BLG in vivo by degrading acidic peptides and releasing immunomodulatory peptides stimulating regulatory T cells, which function as major immunosuppressive agents by secreting IL-10.The mucosal immune system is stimulated daily by the continuous passage of food and microbial antigens. Breakdown of proteins in the gut and activation of T-cell suppression lead to a systemic hyporesponsiveness to ingested protein antigens called oral tolerance. Three basic mechanisms are involved in antigen-driven tolerance: clonal deletion, clonal anergy, and active suppression (13). Active suppression is defined as a state of T-lymphocyte unresponsiveness induced by direct action of regulatory T cells secreting inhibitory factors such as transforming growth factor ␤ and interleukin-10 (IL-10) (18,38,40). Many factors seem to affect the induction of tolerance, including the age of the host, the nature and dosage of the antigen, and the frequency of feeding (1,14,23). The intestinal microbiota has also been found to play a major role in the induction (21,32,34,39) and maintenance (22, 32) of tolerance, but the mechanism has yet to be elucidated.Bifidobacteria and lactobacilli are common anaerobes in the human intestinal microbiota (20), and some of them have been reported to display probiotic properties (26). Probiotics are live microorganisms that when ingested may have positive effects on human health (7). Probiotic bacteria, increasingly used as food supplements, especially in infant formulas, have been found to be transiently present in the intestine when administered daily at high doses (6). The beneficial effects of probiotics on the immune system are believed to be numerous (3, 26), but few studies have focused on their role in induction of oral tolerance. Bifidobacterium infantis has been shown to restore oral tolerance to ovalbumin in monoassociated mice (21, 34), and we have recently reported that oral tolerance to ␤-lactoglobulin (BLG) was strongly induced and maintained in mice monocolonized with Lactobacillus paracasei NCC2461 (32). The mechanisms by which L. paracasei induces and maintains t...

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“…It was demonstrated that L. paracasei NCC2461 participates in -lactoglobulin (BLG) oral tolerance process in mice, attributable to the hydrolysis of BLG into peptides, which stimulate the production of IL-10 ( Fig. 3) [197,198]. Thus, the increased IL-10 production in turn may drive the induction of Tregs in addition to its immunosuppressive effects.…”

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“…Lact . paracasei peptidases have been shown to hydrolyze tryptic -chymotryptic peptides from BLG, releasing numerous small peptides with immunomodulating properties (Prioult et al 2004 ).…”