Enhancement of Mast Cell IL-6 Production by Combined Toll-Like and Nucleotide-Binding Oligomerization Domain-Like Receptor Activation

Abstract

Background: Mast cells respond to bacterial infection by producing mediators that recruit and activate leukocytes, mediate vasodilation and induce bronchoconstriction. These mast cell-driven responses play a crucial role in protective immunity against bacterial infection, but may contribute to bacterial exacerbation of allergic diseases. Bacterial components including peptidoglycan (PGN) and lipopeptides are known to activate receptors such as Toll-like receptors (TLR) and nucleotide-binding oligomerization domain-like receptors (NLR). Since the consequences of mast cell activation by individual or combinations of bacterial components have not been fully characterized, we determined the effects of TLR2 and NLR activation, alone or in combination, on human mast cell mediator production. Methods: Cord blood-derived human mast cells were activated by bacterial PGN, the lipopeptide Pam₃CSK₄ and NLR agonists alone or in combination. Mast cell degranulation, LTC₄ production and the production of cytokines were assessed. Results:PGN and the lipopeptide Pam₃CSK₄ induced human mast cells to produce the pro-inflammatory mediators IL-1β, IL-6, CXCL8 and LTC₄ in addition to anti-inflammatory IL-10. NLR agonists alone did not induce these responses, but significantly and selectively increased Pam₃CSK₄-mediated mast cell IL-6 production. PGN- and Pam₃CSK₄-induced mast cell IL-6, but not IL-1β, production was dependent on adenylyl cyclase activity and could be partially inhibited by the cyclooxygenase inhibitor naproxen. Conclusions: Increased mast cell IL-6 production in response to combined TLR2 and NLR activation could play a role in the protection against bacterial infection, but potentially exacerbate inflammation-dependent conditions. In addition, mast cell IL-6 production is dependent on adenylyl cyclase activity.

Human Cord Blood-Derived Mast Cells Are Activated by the Nod1 Agonist M-TriDAP to Release Pro-Inflammatory Cytokines and Chemokines

“…In agreement with this study, we observed neither histamine nor IL-8 release in CBMCs treated with MDP (data not shown). Previous findings reporting an increased number of Nod2 + mast cells in Crohn's disease patients [27] together with data from Haidl et al [32] , as well as our own data showing that CBMCs from healthy blood donors do not express Nod2, thus might suggest that Nod2-expressing mast cells have a role in chronic diseases, but not in healthy individuals. Our data from co-stimulations are consistent with other studies on monocytes, dendritic and epithelial cells showing a synergistic effect of Nod1 and TLR ligands on production of cytokines regulating the inflammatory response [18,21,33,34] .…”

“…1 and data not shown). It has previously been reported that treating CBMCs with MDP does not generate any detectable mast cell responses [32] . In agreement with this study, we observed neither histamine nor IL-8 release in CBMCs treated with MDP (data not shown).…”

Corecognition of Pathogens: An Important Trigger for Mast Cell Response?

“…Whereas allergens primarily induce degranulation and the release of proinflammatory mediators such as histamine and eicosanoids, bacterial products hardly induce such mediators but instead cytokines needed for the initiation of innate and adaptive immune responses [11] . Thus, the findings of Haidl et al [7] support a regulatory role of the corecognition of pathogens by different pattern recognition receptor family members in mast cells. Selective IL-6 production may be of importance in modulating innate and adaptive immune responses but needs to be analyzed in tissue-derived mast cells as well.…”

“…Haidl et al [7] analyzed the release of pro-and an tiinflammatory mediators using cord blood-derived mast cells following treatment with bacterial-derived PGN, NLR agonists, TLR2 activator triacyl lipopeptide Pam 3 CSK 4 , and a combination of NLR and TLR agonists. The release of IL-1 ␤ , IL-6, CXCL-8, IL-10, and leukotriene C 4 was affected by PGN and Pam 3 CSK 4 without inducing degranulation, but not by NLR agonists.…”

“…Haidl et al [7] conclude that an increased IL-6 production in response to combined TLR2 and NLR activation could play a role in protection against bacterial infection, but could potentially exacerbate inflammation-dependent conditions. Indeed, the corecognition of pathogens by different pattern recognition receptor family members is required to trigger certain responses.…”