Impact of sphingosine kinase 2 deficiency on the development of TNF-alpha-induced inflammatory arthritis.
Impact of sphingosine kinase 2 deficiency on the development of TNF-alpha-induced inflammatory arthritis.
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DOI：
10.1007/s00296-012-2493-2
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发表时间：
2013-10
影响因子：
4
通讯作者：
Gilkeson, Gary S.
中科院分区：
文献类型：
--
作者：
Baker, DeAnna A.;Eudaly, Jackie;Smith, Charles D.;Obeid, Lina M.;Gilkeson, Gary S.
鞘脂是质膜的组成部分，其代谢操作作为许多疾病的潜在治疗方法而受到关注。鞘氨醇激酶 1 (SphK1) 是将鞘氨醇磷酸化为 1-磷酸鞘氨醇 (S1P) 的主要激酶，我们的团队和其他人之前已证明它可以调节炎症性关节炎、炎症性肠病和哮喘的小鼠模型中的炎症。鞘氨醇激酶 2 (SphK2) 对炎症的影响鲜为人知，因为根据疾病模型的不同，报告的结果也不同。在一个模型中，一种特定的 SphK2 抑制剂抑制了炎症性关节炎，而在另一种模型中，SphK2 的 siRNA 敲低则使关节炎恶化。我们之前证明，SphK1 缺陷小鼠可以免受 hTNF-α 诱导的关节炎的发展。为了研究 SphK2 在 TNF-α 诱导的关节炎中的作用，我们开发了 SphK2 缺陷的 hTNF-α 过表达小鼠，并用 SphK2 特异性抑制剂 ABC294640 单独治疗 hTNF-α 小鼠。我们的数据表明，SphK2 的基因抑制不会显着影响炎症性关节炎的严重程度或进展，而 SphK2 的药物抑制会导致关节炎明显更严重。与媒介物治疗的小鼠相比，ABC294640 治疗的小鼠全血和发炎关节组织中的 S1P 含量也较低，但差异并不显着。 ABC294640 治疗不影响发炎关节中的 SphK1 活性，而在关节中检测到很少的 SphK2 活性。我们得出的结论是，SphK2 的遗传抑制与药物抑制中炎症表型的差异可归因于实验中使用的 ABC294640 的量与 ABC294640 对 SphK2 的急性抑制与遗传诱导的终身 SphK2 缺乏的影响。因此，抑制 SphK2 似乎具有促炎作用，而阻断 SphK1 则具有明显的抗炎作用。针对这种鞘氨醇激酶途径的疗法需要针对鞘氨醇激酶具有特异性。
Sphingolipids are components of the plasma membrane whose metabolic manipulation is of interest as a potential therapeutic approach in a number of diseases. Sphingosine kinase 1 (SphK1), the major kinase that phosporylates sphingosine to sphingosine-1-phosphate (S1P), was previously shown by our group and others to modulate inflammation in murine models of inflammatory arthritis, inflammatory bowel disease and asthma. Sphingosine kinase 2’s (SphK2) impact on inflammation is less well known, as variable results were reported depending on the disease model. A specific SphK2 inhibitor inhibited inflammatory arthritis in one model, while siRNA knockdown of SphK2 worsened arthritis in another. We previously demonstrated that SphK1 deficient mice are protected against development of hTNF-α induced arthritis. To investigate the role of SphK2 in TNF-α induced arthritis, we developed SphK2 deficient hTNF-α overexpressing mice and separately treated hTNF-α mice with ABC294640, a SphK2 specific inhibitor. Our data show that genetic inhibition of SphK2 did not significantly impact the severity or progression of inflammatory arthritis, while pharmacologic inhibition of SphK2 led to significantly more severe arthritis. Compared to vehicle-treated mice, ABC294640 treated mice also had less S1P in whole blood and inflamed joint tissue, although the differences were not significant. ABC294640 treatment did not affect SphK1 activity in the inflamed joint while little SphK2 activity was detected in the joint. We conclude that the differences in the inflammatory phenotype in genetic inhibition vs. pharmacologic inhibition of SphK2 can be attributed to the amount of ABC294640 used in the experiments versus the impact of acute inhibition of SphK2 with ABC294640 vs. genetically-induced life-long SphK2 deficiency. Thus, inhibition of SphK2 appears to be proinflammatory in contrast to the clear anti-inflammatory effects of blocking SphK1. Therapies directed at this sphingosine kinase pathways will need to be specific in their targeting of sphingosine kinases.
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