A TLR2 ligand suppresses allergic inflammatory reactions by acting directly on mast cells.
BACKGROUND
Although much attention has been focused on the anti-allergic effects of probiotics, their mode of action is not fully understood. Mast cells, which play a central role in inducing allergic inflammation, are potential targets of probiotics given the recent discovery that they express Toll-like receptors (TLRs), the pattern recognition receptors for microbial components. In this study, we examined whether allergic reactions of mast cells are modulated by stimulation through TLR2.


METHODS
The effects on mast cells of the synthetic TLR2 ligand Pam3CSK4 and Bifidobacterium pseudocatenulatum JCM 7041 were evaluated in vitro. Furthermore, the effects of Pam3CSK4 on mast cell-induced increase in vascular permeability in vivo were investigated by employing mast cell-deficient W/W(v) mice into which IgE-sensitized mouse bone marrow-derived mast cells were transferred.


RESULTS
Pam3CSK4 and Bifidobacterium pseudocatenulatum JCM 7041 suppressed degranulation of IgE-sensitized mast cells upon antigen stimulation in vitro. Pam3CSK4 also suppressed leukotriene C(4) production triggered by engagement of the high-affinity IgE receptor, FcepsilonRI. Intracellular Ca(2+) mobilization and phosphorylation of Erk were suppressed by pretreatment with Pam3CSK4, suggesting that the TLR2 ligand suppresses activation of mast cells by interrupting FcepsilonRI-mediated intracellular signaling. Pam3CSK4 treatment of bone marrow-derived mast cells reduced the increase in vascular permeability in recipient W/W(v) mice upon intravenous injection of antigen; the decrease was by about half, in a TLR-dependent manner.


CONCLUSIONS
Collectively, these results demonstrate that the FcepsilonRI-mediated inflammatory responses of mast cells are suppressed by stimulation through TLR2, suggesting that probiotics exert potential anti-allergic effects, at least in part, through direct effects on mast cells.
Kasakura
Kazumi
K
Laboratory of Biological Chemistry on Food Functionalities, Department of Food Science and Technology, College of Bioresource Sciences, Nihon University, Kanagawa 252-8510, Japan. ktaka@brs.nihon-u.ac.jp
Takahashi
Kyoko
K
Aizawa
Tomoyuki
T
Hosono
Akira
A
Kaminogawa
Shuichi
S
D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D001644:Bifidobacterium / Q000276:immunology*; D002199:Capillary Permeability / Q000187:drug effects / Q000276:immunology; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D007073:Immunoglobulin E / Q000276:immunology*; D056747:Immunomodulation; D055666:Lipopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D019936:Probiotics; D017455:Receptors, IgE / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors*
D000942:Antigens, Bacterial; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; D017455:Receptors, IgE; D051195:Toll-Like Receptor 2; D007073:Immunoglobulin E