Department of Dermatology, University of Münster, Von Esmarch-Str. 58, D-48149 Münster, Germany.
Adv Exp Med Biol. 2010;681:107-16. doi: 10.1007/978-1-4419-6354-3_8.
During the last two decades a significant number of investigations has established the fact that α-Melanocyte-stimulating hormone (α-MSH) is a potent anti-inflammatory mediator. The anti-inflammatory effects of α-MSH can be elicited via melanocortin receptors (MC-Rs) broadly expressed in a number of tissues ranging from the central nervous system to cells of the immune system and on resident somatic cells of peripheral tissues. α-MSH affects various pathways regulating inflammatory responses such as NF-κB activation, expression of adhesion molecules, inflammatory cytokines, chemokine receptors, T-cell proliferation and activity and inflammatory cell migration. In vivo α-MSH has been shown to be anti-inflammatory as well in animal models of fever, irritant and allergic contact dermatitis, cutaneous vasculitis, fibrosis, in ocular, gastrointestinal, brain and allergic airway inflammation and arthritis. A broad range of effects of α-MSH exerted beyond the field of inflammation, its pigmentory capacity being only the most visible aspect, has been one of the major impediments limiting the use of α-MSH in human inflammatory disorders. Interestingly KPV, C-terminal tripeptide of α-MSH, which lacks the entire sequence motif required for binding to any of the known MC-Rs, retains almost all of the anti-inflammatory capacity of the full hormone, but in its activities display a lack of any pigmentory action. While the exact signaling mechanism utilized by KPV and related peptides currently is unknown it has been demonstrated already that significant similarities between anti-inflammatory signaling of α-MSH and those short peptides exist. These α-MSH related tripeptides thus may be useful alternatives for anti-inflammatory peptide therapy. KdPT, a derivative of KPV corresponding to IL-1β(193-195), currently is emerging as another tripeptide with potent anti-inflammatory effects. A more limited spectrum of biologic activities, potentially advantageous physicochemical, pharmacokinetic and pharmacodynamic properties as well as the expectation of low costs for pharmaceutical production make these agents interesting candidates for the treatment of immune-mediated inflammatory skin and bowel diseases, allergic asthma and arthritis.
在过去的二十年中，大量的研究已经证实，α-黑色素细胞刺激素（α-MSH）是一种有效的抗炎介质。α-MSH 的抗炎作用可以通过广泛表达于中枢神经系统到免疫系统细胞以及外周组织常驻体细胞的黑色素皮质素受体（MC-R）来引发。α-MSH 影响调节炎症反应的各种途径，如 NF-κB 激活、黏附分子表达、炎症细胞因子、趋化因子受体、T 细胞增殖和活性以及炎症细胞迁移。在体内，α-MSH 已被证明在发热、刺激性和过敏性接触性皮炎、皮肤血管炎、纤维化、眼部、胃肠道、大脑和过敏性气道炎症和关节炎的动物模型中具有抗炎作用。除了在炎症领域之外，α-MSH 还具有广泛的作用，其色素形成能力只是最明显的方面，这一直是限制 α-MSH 在人类炎症性疾病中应用的主要障碍之一。有趣的是，α-MSH 的 C 端三肽 KPV 缺乏与任何已知 MC-R 结合所需的整个序列基序，但保留了完整激素几乎所有的抗炎能力，但在其活性中缺乏任何色素形成作用。虽然目前尚不清楚 KPV 和相关肽利用的确切信号机制，但已经证明，α-MSH 和这些短肽的抗炎信号之间存在显著的相似性。这些 α-MSH 相关的三肽因此可能是抗炎肽治疗的有用替代品。KdPT 是 KPV 的衍生物，对应于 IL-1β(193-195)，目前作为另一种具有强大抗炎作用的三肽出现。其生物活性谱更有限、潜在有利的理化、药代动力学和药效学特性以及预期用于药物生产的低成本，使得这些药物成为治疗免疫介导的炎症性皮肤和肠道疾病、过敏性哮喘和关节炎的有前途的候选药物。
