Institute for Immunology, Johannes Gutenberg University, Mainz, Germany.
J Innate Immun. 2009;1(6):582-91. doi: 10.1159/000231973. Epub 2009 Jul 30.
The triggering receptor expressed on myeloid cells 1 (TREM-1) is involved in the innate inflammatory response to microbial infections. Activation and expression of TREM-1 by polymorphonuclear neutrophils (PMN) occurs in concert with Toll-like receptors (TLR) such as TLR4 for bacterial lipopolysaccharide. However, it is currently unclear how this is mediated on a molecular level. Using pharmacological inhibitors and Western blot analysis we demonstrate that phosphatidyl inositide 3-kinase, phospholipase C and the mitogen-activated kinase p38MAPK are essential for the TREM-1- and TLR4-induced oxidative burst of human PMN. The activation of protein kinase B and extracellular signal-related kinase show characteristic phosphorylation patterns upon single or co-ligation indicating individual activation pathways of both receptors. Taken together, we provide new insights into the mechanisms how TREM-1 and TLR interact creating synergistic activation in PMN. These results shed a new light on our understanding of how the innate inflammatory responses are regulated and might contribute to the development of future concepts for the treatment of severe inflammatory conditions such as sepsis.
髓系细胞表达的触发受体 1（TREM-1）参与对微生物感染的固有炎症反应。多形核粒细胞（PMN）中 TREM-1 的激活和表达与 Toll 样受体（TLR）如 TLR4 协同发生，用于细菌脂多糖。然而，目前尚不清楚这在分子水平上是如何介导的。使用药理学抑制剂和 Western blot 分析，我们证明磷脂酰肌醇 3-激酶、磷脂酶 C 和丝裂原活化蛋白激酶 p38MAPK 对于 TREM-1 和 TLR4 诱导的人 PMN 的氧化爆发是必需的。蛋白激酶 B 和细胞外信号相关激酶的激活在单或共交联时表现出特征性的磷酸化模式，表明两个受体的单独激活途径。总之，我们提供了关于 TREM-1 和 TLR 如何相互作用以在 PMN 中产生协同激活的新见解。这些结果为我们理解固有炎症反应如何受到调节提供了新的认识，并可能有助于为严重炎症性疾病（如败血症）的治疗开发未来的概念。
