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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >IL-15 mediates immune inflammatory hypernociception by triggering a sequential release of IFN-gamma, endothelin, and prostaglandin
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IL-15 mediates immune inflammatory hypernociception by triggering a sequential release of IFN-gamma, endothelin, and prostaglandin

机译：IL-15通过触发IFN-γ，内皮素和前列腺素的顺序释放来介导免疫炎性高伤害感受

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摘要

IL-15 is closely associated with inflammatory diseases. IL-15 targeting is effective in treating experimental and clinical rheumatoid arthritis (RA). Because hyperalgesia accompanies RA, we investigated the ability of IL-15 to induced nociceptor sensitization (hypernociception). We report here that IL-15 induced time- and dose-dependent mechanical hypernociception in mice. IL-15-induced hypernociception was inhibited by treatment with a dual endothelin receptor type A (ETA)/endothelin receptor type B (ETB) antagonist (bosentan), ETA receptor antagonist (BQ123), or cyclooxygenase inhibitor (indomethacin). Moreover, IL-15 failed to induce hypernociception in IFN-gamma(-/-) mice, suggesting that IL-15 mediated hypernociception via an IFN-gamma-, endothelin (ET)-, and prostaglandin-dependent pathway. Consistent with this finding, IFN-gamma and ET-1 induced dose- and time-dependent mechanical hypernociception that was inhibited by BQ123 or indomethacin but not BQ788 (an ETB receptor antagonist). IFN-gamma induced the production of ET-1 and the expression of its mRNA precursor (preproET-1, PPET-1). Moreover, IL-15 also induced ET-1 production and PPET-1 mRNA expression in an IFN-gamma-dependent manner. Prostaglandin E-2 (PGE(2)) production was induced by IL-15, IFN-gamma, or ET-1. We also found that hypernociception induced by ovalbumin (OVA) in OVA-immunized mice was significantly diminished by treatment with sIL-15R alpha (soluble IL-15 receptor a-chain), bosentan, BQ123, or indomethacin. Furthermore, OVA challenge induced the expression of PPET-1 mRNA in WT mice but not in IFN-gamma(-/-) mice. The PPET-1 mRNA expression was also inhibited by sIL-15Ra pretreatment. Therefore, our results demonstrate the sequential mechanical hypernociceptive effect of IL-15 -> IFN-gamma -> ET-1 -> PGE(2) and suggest that these molecules may be targets of therapeutic intervention in antigen-induced hypernociception.
机译：IL-15与炎性疾病密切相关。 IL-15靶向可有效治疗实验和临床类风湿关节炎（RA）。由于痛觉过敏伴随RA，我们研究了IL-15诱导伤害感受器致敏（痛觉过敏）的能力。我们在这里报告IL-15诱导小鼠时间和剂量依赖的机械性神经痛。通过使用双重内皮素A型受体（ETA）/内皮素B型受体（ETB）拮抗剂（波生坦），ETA受体拮抗剂（BQ123）或环氧合酶抑制剂（吲哚美辛）抑制IL-15诱导的痛觉过敏。此外，IL-15未能在IFN-γ（-/-）小鼠中诱导痛觉超敏，表明IL-15通过IFN-γ-，内皮素（ET）-和前列腺素依赖性途径介导的痛觉超敏。与此发现一致，IFN-γ和ET-1诱导了剂量和时间依赖性的机械性神经痛，并受到BQ123或消炎痛的抑制，但不受BQ788（ETB受体拮抗剂）的抑制。 IFN-γ诱导ET-1的产生及其mRNA前体（preproET-1，PPET-1）的表达。此外，IL-15还以IFN-γ依赖性的方式诱导ET-1的产生和PPET-1 mRNA的表达。 IL-15，IFN-γ或ET-1诱导了前列腺素E-2（PGE（2））的产生。我们还发现，通过用sIL-15Rα（可溶性IL-15受体a链），波生坦，BQ123或消炎痛治疗，卵白蛋白（OVA）诱发的卵白蛋白（OVA）诱发的痛觉过敏显着减少。此外，OVA攻击诱导WT小鼠中PPET-1 mRNA的表达，但不诱导IFN-γ（-/-）小鼠中。 sIL-15Ra预处理也抑制了PPET-1 mRNA的表达。因此，我们的结果证明了IL-15->IFN-γ-> ET-1-> PGE（2）的顺序机械性痛觉过敏作用，并表明这些分子可能是抗原诱导的痛觉过敏的治疗干预目标。

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