Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.
Int Arch Allergy Immunol. 2011;154(3):227-35. doi: 10.1159/000321109. Epub 2010 Sep 21.
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.
Cord blood-derived human mast cells were activated by bacterial PGN, the lipopeptide Pam(3)CSK(4) and NLR agonists alone or in combination. Mast cell degranulation, LTC(4) production and the production of cytokines were assessed.
PGN and the lipopeptide Pam(3)CSK(4) induced human mast cells to produce the pro-inflammatory mediators IL-1β, IL-6, CXCL8 and LTC(4) in addition to anti-inflammatory IL-10. NLR agonists alone did not induce these responses, but significantly and selectively increased Pam(3)CSK(4)-mediated mast cell IL-6 production. PGN- and Pam(3)CSK(4)-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.
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.
肥大细胞通过产生招募和激活白细胞的介质、介导血管扩张和诱导支气管收缩来响应细菌感染。这些由肥大细胞驱动的反应在对抗细菌感染的保护性免疫中起着至关重要的作用，但也可能导致细菌加重过敏疾病。已知细菌成分，包括肽聚糖（PGN）和脂肽，可激活受体，如 Toll 样受体（TLR）和核苷酸结合寡聚化结构域样受体（NLR）。由于单个或组合的细菌成分激活肥大细胞的后果尚未完全表征，因此我们确定了 TLR2 和 NLR 激活，单独或联合使用，对人肥大细胞介质产生的影响。
单独或联合使用细菌 PGN、脂肽 Pam(3)CSK(4)和 NLR 激动剂激活脐带血来源的人肥大细胞。评估肥大细胞脱颗粒、LTC(4)产生和细胞因子的产生。
PGN 和脂肽 Pam(3)CSK(4)诱导人肥大细胞产生促炎介质 IL-1β、IL-6、CXCL8 和 LTC(4)，以及抗炎性 IL-10。NLR 激动剂单独使用不会引起这些反应，但显着且选择性地增加 Pam(3)CSK(4)介导的肥大细胞 IL-6 产生。PGN 和 Pam(3)CSK(4)诱导的肥大细胞 IL-6，但不是 IL-1β，产生依赖于腺苷酸环化酶活性，并且可以部分被环氧化酶抑制剂萘普生抑制。
对 TLR2 和 NLR 联合激活的肥大细胞 IL-6 产生增加可能在对抗细菌感染的保护中起作用，但可能加重炎症依赖性疾病。此外，肥大细胞 IL-6 的产生依赖于腺苷酸环化酶活性。
