Activation of Murine Macrophages via TLR2 and TLR4 Is Negatively Regulated by a Lyn/PI3K Module and Promoted by SHIP1
Activation of Murine Macrophages via TLR2 and TLR4 Is Negatively Regulated by a Lyn/PI3K Module and Promoted by SHIP1
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DOI：
10.4049/jimmunol.0901423
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发表时间：
2010-05-15
影响因子：
4.4
通讯作者：
Huber, Michael
中科院分区：
文献类型：
--
作者：
Keck, Simone;Freudenberg, Marina;Huber, Michael
Src家族激酶参与细胞信号传导的许多方面。我们在这项研究中表明，Src家族激酶林恩负调节TLR信号在小鼠骨髓源性巨噬细胞（BMM Phi s）和体内。与野生型（WT）BMM Phi相比，LPS刺激的林恩（-/-）BMM Phi产生显著更多的IL-6、TNF-α和IFN-α/β，表明林恩能够控制TLR 4下游的MyD 88和TRIF依赖性信号传导途径。CD 14不参与这种类型的调节。此外，林恩减弱了BMM Phi中响应于TLR 2配体FSL-1的促炎细胞因子产生，但不响应于TLR 3（dsRNA）或TLR 9（CpG 1668）的配体。与这些体外实验一致，在i.注射LPS或FSL-1。虽然林恩在TLR 4和TLR 2下游明显起负调节作用，但与先前提出的不同，它并不阻止LPS耐受的诱导。在WT和林恩（-/-）BMM Phi中以及体内，用低剂量LPS刺激导致随后用高剂量LPS刺激后促炎细胞因子的产生减少。从机制上讲，林恩与PI 3 K相互作用;相关性，PI 3 K抑制导致LPS触发的细胞因子产生增加。在该细胞系中，SHIP 1（-/-）BMM Phi s发挥增强的PI 3 K-途径活化，产生比WT BMM Phi s更少的细胞因子。这些数据表明，林恩介导的TLR信号传导的负调控至少部分地通过PI 3 K进行。免疫学杂志，2010，184：5809-5818。
Src family kinases are involved in a plethora of aspects of cellular signaling. We demonstrate in this study that the Src family kinase Lyn negatively regulates TLR signaling in murine bone marrow-derived macrophages (BMM Phi s) and in vivo. LPS-stimulated Lyn(-/-) BMM Phi s produced significantly more IL-6, TNF-alpha, and IFN-alpha/beta compared with wild type (WT) BMM Phi s, suggesting that Lyn is able to control both MyD88- and TRIF-dependent signaling pathways downstream of TLR4. CD14 was not involved in this type of regulation. Moreover, Lyn attenuated proinflammatory cytokine production in BMM Phi s in response to the TLR2 ligand FSL-1, but not to ligands for TLR3 (dsRNA) or TLR9 (CpG 1668). In agreement with these in vitro experiments, Lyn-deficient mice produced higher amounts of proinflammatory cytokines than did WT mice after i. v. injection of LPS or FSL-1. Although Lyn clearly acted as a negative regulator downstream of TLR4 and TLR2, it did not, different from what was proposed previously, prevent the induction of LPS tolerance. Stimulation with a low dose of LPS resulted in reduced production of proinflammatory cytokines after subsequent stimulation with a high dose of LPS in both WT and Lyn(-/-) BMM Phi s, as well as in vivo. Mechanistically, Lyn interacted with PI3K; in correlation, PI3K inhibition resulted in increased LPS-triggered cytokine production. In this line, SHIP1(-/-) BMM Phi s, exerting enhanced PI3K-pathway activation, produced fewer cytokines than did WT BMM Phi s. The data suggest that the Lyn-mediated negative regulation of TLR signaling proceeds, at least in part, via PI3K. The Journal of Immunology, 2010, 184: 5809-5818.