Sphingosine kinase-1 is required for toll mediated beta-defensin 2 induction in human oral keratinocytes.
Sphingosine kinase-1 is required for toll mediated beta-defensin 2 induction in human oral keratinocytes.
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DOI：
10.1371/journal.pone.0011512
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发表时间：
2010-07-09
期刊：
影响因子：
3.7
通讯作者：
Kinane DF
中科院分区：
文献类型：
--
作者：
Benakanakere MR;Zhao J;Galicia JC;Martin M;Kinane DF
宿主对入侵病原体的防御是由包括toll样受体（TLRs）在内的多种受体触发的。tlr的激活是启动先天、炎症和抗菌防御机制的关键步骤。人β-防御素2 （HBD-2）是一种阳离子抗菌肽，在革兰氏阴性细菌干扰下在许多细胞中分泌。刺激各种tlr已被证明可在口腔角质形成细胞中诱导HBD-2，但这种诱导的潜在细胞机制尚不清楚。本研究表明，鞘氨酸激酶-1 （Sphk-1）介导了HBD-2的诱导，并通过磷酸肌苷激酶3-激酶（PI3K）依赖途径抑制糖原合成酶激酶3- β (GSK-3β)增强了HBD-2的诱导。Sphk-1药理学抑制剂剂量依赖性地抑制HBD-2的分泌。有趣的是，SB 216763或RNA干扰对GSK-3β的抑制增强了HBD-2的诱导。过度表达Sphk-1并同时抑制GSK-3β可增强口腔角质形成细胞中β-防御素-2的诱导。组成活性的GSK-3β (S9A)异位表达消除了HBD-2，而激酶无活性的GSK-3β (R85A)诱导了更高量的HBD-2。这些数据表明Sphk-1在口腔角化细胞中参与HBD-2调控，这也涉及PI3K、AKT、GSK-3β和ERK 1/2的激活。因此，我们揭示了调节HBD-2的收费信号分子的复杂关系和途径，这可能具有治疗潜力。
Host defense against invading pathogens is triggered by various receptors including toll-like receptors (TLRs). Activation of TLRs is a pivotal step in the initiation of innate, inflammatory, and antimicrobial defense mechanisms. Human β-defensin 2 (HBD-2) is a cationic antimicrobial peptide secreted upon Gram-negative bacterial perturbation in many cells. Stimulation of various TLRs has been shown to induce HBD-2 in oral keratinocytes, yet the underlying cellular mechanisms of this induction are poorly understood. Here we demonstrate that HBD-2 induction is mediated by the Sphingosine kinase-1 (Sphk-1) and augmented by the inhibition of Glycogen Synthase Kinase-3β (GSK-3β) via the Phosphoinositide 3-kinase (PI3K) dependent pathway. HBD-2 secretion was dose dependently inhibited by a pharmacological inhibitor of Sphk-1. Interestingly, inhibition of GSK-3β by SB 216763 or by RNA interference, augmented HBD-2 induction. Overexpression of Sphk-1 with concomitant inhibition of GSK-3β enhanced the induction of β-defensin-2 in oral keratinocytes. Ectopic expression of constitutively active GSK-3β (S9A) abrogated HBD-2 whereas kinase inactive GSK-3β (R85A) induced higher amounts of HBD-2. These data implicate Sphk-1 in HBD-2 regulation in oral keratinocytes which also involves the activation of PI3K, AKT, GSK-3β and ERK 1/2. Thus we reveal the intricate relationship and pathways of toll-signaling molecules regulating HBD-2 which may have therapeutic potential.
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影响因子：
4.4
作者：
Burns, Elia;Eliyahu, Tal;Nussbaum, Gabriel
通讯作者：
Nussbaum, Gabriel
DOI：
10.1126/science.1176709
发表时间：
2009-09-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hait NC;Allegood J;Maceyka M;Strub GM;Harikumar KB;Singh SK;Luo C;Marmorstein R;Kordula T;Milstien S;Spiegel S
通讯作者：
Spiegel S
影响因子：
64.8
作者：
Foster, Simmie L.;Hargreaves, Diana C.;Medzhitov, Ruslan
通讯作者：
Medzhitov, Ruslan
影响因子：
8.6
作者：
Garg, Sanjay K.;Santucci, Marilina B.;Fraziano, Maurizio
通讯作者：
Fraziano, Maurizio
影响因子：
4.8
作者：
Chong, Kong T.;Xiang, Liangbin;Wang, Xiaohong;Jun, Eunjoo L.;Xi, Long-fu;Schweinfurth, John M.
通讯作者：
Schweinfurth, John M.