Distinct Roles of Sphingosine Kinase 1 and 2 in Murine Collagen-Induced Arthritis
Distinct Roles of Sphingosine Kinase 1 and 2 in Murine Collagen-Induced Arthritis
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DOI：
10.4049/jimmunol.0804376
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发表时间：
2009-08-01
影响因子：
4.4
通讯作者：
Leung, Bernard P.
中科院分区：
文献类型：
--
作者：
Lai, Wen-Qi;Irwan, Anastasia Windy;Leung, Bernard P.
鞘氨醇激酶(SphK)将鞘氨醇磷酸化为鞘氨醇-1-磷酸(S1P)。Sip在血管生成、炎症和各种病理条件中起关键作用。到目前为止，已经鉴定出两种哺乳动物同工酶，SphK1和SphK2。虽然SphK1和SphK2在总体上具有同源性，并产生共同的产物SIP，但已有研究表明，它们具有不同的独特和独立的功能。在这项研究中，我们通过特定的小干扰RNA(SiRNA)下调SphK1和SphK2的同工酶，研究了SphK1和SphK2在小鼠胶原性关节炎模型中的作用。预防性ip。与对照siRNA接受者相比，注射SphK1 siRNA显著降低了发病率、疾病严重性和关节炎症。经SphK1 siRNA治疗后，血清中的SIP、IL-6、TNF-α、ILFN-γ和IgG2a抗胶原抗体水平也明显下降。体外分析表明，SphK siRNA处理的小鼠的胶原特异性促炎/Th1细胞因子(IL-6、肿瘤坏死因子-α、干扰素-γ)的释放受到显著抑制。有趣的是，与对照组相比，接受SphK2 Arna治疗的小鼠发生了更具侵袭性的疾病；血清中IL-6、TNF-α和干扰素-γ水平更高；在体外，促炎症细胞因子产生胶原。总之，这些结果表明，SphKI和SphK2通过调节促炎细胞因子的释放和T细胞反应，在炎症性关节炎的发展过程中发挥着不同的免疫调节作用。这些发现增加了专门针对SphK1活性的药物在炎症性关节炎治疗中发挥有益作用的可能性。免疫学杂志，2009,183：2097-2103。
Sphingosine kinase (SphK) phosphorylates sphingosine into sphingosine-1-phosphate (S1P). SIP plays a critical role in angiogenesis, inflammation, and various pathologic conditions. To date, two mammalian isoenzymes, SphK1 and SphK2, have been identified. Although both SphK1 and SphK2 share overall homology and produce the common product, SIP, it has been proposed they display different unique and separate functions. In this study, we examined the role of SphK1 and SphK2 in a murine collagen-induced arthritis model by down-regulating each isoenzyme via specific small interfering RNA (siRNA). Prophylactic i.p. administration of SphK1 siRNA significantly reduced the incidence, disease severity, and articular inflammation compared with control siRNA recipients. Treatment of SphK1 siRNA also down-regulated serum levels of SIP, IL-6, TNF-alpha, ILFN-gamma, and IgG2a anti-collagen Ab. Ex vivo analysis demonstrated significant suppression of collagen-specific proinflammatory/Th1 cytokine (IL-6, TNF-alpha, IFN-gamma) release in SphK siRNA-treated mice. Interestingly, mice received with SphK2 ARNA develop more aggressive disease; higher serum levels of IL-6, TNF-alpha, and IFN-gamma; and proinflammatory cytokine production to collagen in vitro when compared with control siRNA recipients. Together, these results demonstrate the distinct immunomodulatory roles of SphKI and SphK2 in the development of inflammatory arthritis by regulating the release of proinflammatory cytokines and T cell responses. These findings raise the possibility that drugs which specifically target SphK1 activity may play a beneficial role in the treatment of inflammatory arthritis. The Journal of Immunology, 2009, 183: 2097-2103.