Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan
Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
J Immunol. 2019 May 1;202(9):2609-2615. doi: 10.4049/jimmunol.1801426. Epub 2019 Mar 22.
Cholecystokinin (CCK) is a peptide hormone that functions in digestive organs and the CNS. We previously showed that CCK downregulates peripheral pruritus by suppressing degranulation of mast cells. In this study, we demonstrated that CCK octapeptide (CCK8) was constitutively expressed in the epidermis of normal skin, whereas its expression was lost in acanthotic lesions of psoriasis. In contrast, CCKA receptor (CCKAR), a high-affinity receptor for CCK, was constitutively expressed in the epidermis of psoriatic skin lesions. Expression of CCK was also reduced in skin lesions of an imiquimod (IMQ)-induced psoriatic mouse model. Notably, the expression level of CCK inversely correlated with the severity of epidermal inflammation, raising the possibility that CCK from epidermal keratinocytes suppresses the psoriatic inflammation. To verify this hypothesis, we investigated the effects of sulfated CCK octapeptide (CCK8S) on the development of IMQ-induced psoriatic inflammation. i.p. injection of CCK8S suppressed the IMQ-induced psoriatic inflammation accompanied by reduced mRNA expression of IL-17, IL-22, and IL-6 but not of IL-23. The suppressive effect of CCK8S was completely restored by administration of CCKAR antagonist. In vitro studies showed that exogenous CCK8S suppressed IL-6 production in CCKAR-expressing cultured human keratinocytes, and blocking the endogenous CCK signaling with CCKAR antagonist markedly enhanced IL-6 production. When keratinocytes were stimulated with IL-17, the expression of endogenous CCK was significantly decreased. These findings suggest that CCK physiologically functions as a negative regulator of keratinocyte-based inflammation in an autocrine or paracrine manner, although decreased CCK may pathologically contribute to continuous and aggravated skin lesions such as psoriasis.
胆囊收缩素（CCK）是一种在消化器官和中枢神经系统中起作用的肽激素。我们之前表明，CCK 通过抑制肥大细胞脱颗粒来下调外周瘙痒。在这项研究中，我们证明 CCK 八肽（CCK8）在正常皮肤的表皮中持续表达，而在银屑病的棘层肥厚病变中其表达丢失。相比之下，CCK 受体（CCKAR），CCK 的高亲和力受体，在银屑病皮损的表皮中持续表达。CCK 的表达也在咪喹莫特（IMQ）诱导的银屑病小鼠模型的皮肤损伤中减少。值得注意的是，CCK 的表达水平与表皮炎症的严重程度呈反比，这表明表皮角质形成细胞中的 CCK 抑制银屑病炎症。为了验证这一假说，我们研究了硫酸化 CCK 八肽（CCK8S）对 IMQ 诱导的银屑病炎症发展的影响。CCK8S 的腹腔注射抑制了 IMQ 诱导的银屑病炎症，同时降低了 IL-17、IL-22 和 IL-6 的 mRNA 表达，但不降低 IL-23 的表达。CCKAR 拮抗剂的给药完全恢复了 CCK8S 的抑制作用。体外研究表明，外源性 CCK8S 抑制 CCKAR 表达的培养人角质形成细胞中 IL-6 的产生，并且用 CCKAR 拮抗剂阻断内源性 CCK 信号显著增强了 IL-6 的产生。当角质形成细胞受到 IL-17 刺激时，内源性 CCK 的表达明显减少。这些发现表明 CCK 以自分泌或旁分泌的方式作为角质形成细胞炎症的负调节剂发挥生理作用，尽管 CCK 的减少可能在病理上导致连续和加重的皮肤病变，如银屑病。
