Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan.
J Neurosci. 2012 Aug 15;32(33):11330-42. doi: 10.1523/JNEUROSCI.0677-12.2012.
Interleukin (IL)-1β and IL-18 play critical roles in the induction of chronic pain hypersensitivity. Their inactive forms are activated by caspase-1. However, little is known about the mechanism underlying the activation of pro-caspase-1. There is increasing evidence that cathepsin B (CatB), a typical lysosomal cysteine protease, is involved in the pro-caspase-1 activation and the subsequent maturation of IL-1β and IL-18. In this context, CatB is considered to be an important molecular target to control chronic pain. However, no information is currently available about the role of CatB in chronic pain hypersensitivity. We herein show that CatB deficiency or the intrathecal administration of CA-074Me, a specific CatB inhibitor, significantly inhibited the induction of complete Freund's adjuvant-induced tactile allodynia in mice without affecting peripheral inflammation. In contrast, CatB deficiency did not affect the nerve injury-induced tactile allodynia. Furthermore, CatB deficiency or CA-074Me treatment significantly inhibited the maturation and secretion of IL-1β and IL-18 by cultured microglia following treatment with the neuroactive glycoprotein chromogranin A (CGA), but not with ATP. Moreover, the IL-1β expression in spinal microglia and the induction of tactile allodynia following the intrathecal administration of CGA depended on CatB, whereas those induced by the intrathecal administration of ATP or lysophosphatidic acid were CatB independent. These results strongly suggest that CatB is an essential enzyme for the induction of chronic inflammatory pain through its activation of pro-caspase-1, which subsequently induces the maturation and secretion of IL-1β and IL-18 by spinal microglia. Therefore, CatB-specific inhibitors may represent a useful new strategy for treating inflammation-associated pain.
白细胞介素 (IL)-1β 和 IL-18 在诱导慢性痛觉过敏中发挥关键作用。它们的无活性形式被半胱天冬酶-1 激活。然而，关于前体半胱天冬酶-1 激活的机制知之甚少。越来越多的证据表明，组织蛋白酶 B (CatB)，一种典型的溶酶体半胱氨酸蛋白酶，参与前体半胱天冬酶-1 的激活以及随后的 IL-1β 和 IL-18 的成熟。在这种情况下，CatB 被认为是控制慢性疼痛的重要分子靶标。然而，目前尚无关于 CatB 在慢性痛觉过敏中的作用的信息。我们在此表明，CatB 缺乏或鞘内给予 CA-074Me（一种特异性 CatB 抑制剂）可显著抑制完全弗氏佐剂诱导的小鼠触觉过敏的诱导，而不影响外周炎症。相比之下，CatB 缺乏并不影响神经损伤引起的触觉过敏。此外，CatB 缺乏或 CA-074Me 处理显著抑制了神经活性糖蛋白嗜铬粒蛋白 A (CGA)处理后培养的小胶质细胞中 IL-1β 和 IL-18 的成熟和分泌，但不影响 ATP。此外，脊髓小胶质细胞中 IL-1β 的表达和鞘内给予 CGA 诱导的触觉过敏依赖于 CatB，而鞘内给予 ATP 或溶血磷脂酸诱导的则不依赖于 CatB。这些结果强烈表明，CatB 是通过激活前体半胱天冬酶-1 诱导慢性炎症性疼痛的必需酶，随后诱导脊髓小胶质细胞中 IL-1β 和 IL-18 的成熟和分泌。因此，CatB 特异性抑制剂可能代表治疗与炎症相关疼痛的一种有用的新策略。
