Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
J Immunol. 2010 Aug 1;185(3):1887-93. doi: 10.4049/jimmunol.1001227. Epub 2010 Jul 7.
IL-1 is a proinflammatory cytokine consisting of two molecular species, IL-1alpha and IL-1beta, and IL-1R antagonist (gene: Il1rn) is the endogenous suppressor. Il1rn(-/-) mice spontaneously develop autoimmune diseases, such as arthritis and aortitis, and a dermatitis that histologically resembles human psoriasis. The pathogenic mechanisms underlying this dermatitis, however, remain to be elucidated. In this study, we demonstrated that the production of inflammatory cytokines and chemokines was enhanced at the site of inflammation. The development of dermatitis was completely suppressed in Tnfsf1a(-/-) but not in Il6(-/-) mice, similar to that observed in arthritis and aortitis. However, IL-17 deficiency did not affect the development of dermatitis at all, in clear contrast to that of arthritis and aortitis. Different from arthritis and aortitis, adoptive transfer of Il1rn(-/-) T cells did not induce dermatitis in the recipient SCID mice and skin lesions developed in Il1rn(-/-) SCID mice, indicating that T cells are not involved in the development of skin lesions. In support for this, bone marrow cell transplantation experiments showed that TNF produced by skin residential cells, but not bone marrow cell-derived cells, was important for the development of dermatitis. Furthermore, we showed that IL-1 directly enhanced TNF and chemokine expression in keratinocytes. These observations suggest that excess IL-1 signaling directly activates keratinocytes to produce TNF and chemokines, resulting in the development of psoriasis-like skin lesions without the involvement of autoimmunity in Il1rn(-/-) mice.
IL-1 是一种促炎细胞因子，由两种分子形式组成，即 IL-1alpha 和 IL-1beta，而 IL-1R 拮抗剂（基因：Il1rn）是内源性抑制剂。Il1rn(-/-) 小鼠会自发地患上自身免疫性疾病，如关节炎和动脉炎，以及一种组织学上类似于人类银屑病的皮炎。然而，这种皮炎的发病机制仍有待阐明。在这项研究中，我们证明了炎症部位促炎细胞因子和趋化因子的产生增强了。在 Tnfsf1a(-/-) 小鼠中，而不是在 Il6(-/-) 小鼠中，皮炎的发展完全受到抑制，与关节炎和动脉炎的情况相似。然而，IL-17 缺陷对皮炎的发展完全没有影响，这与关节炎和动脉炎形成鲜明对比。与关节炎和动脉炎不同，在接受 SCID 小鼠中，Il1rn(-/-) T 细胞的过继转移并没有引起皮炎，而在 Il1rn(-/-) SCID 小鼠中，皮肤病变会发展，这表明 T 细胞不参与皮肤病变的发展。为了支持这一观点，骨髓细胞移植实验表明，皮肤常驻细胞产生的 TNF，而不是骨髓细胞衍生的细胞产生的 TNF，对皮炎的发展很重要。此外，我们还表明，IL-1 直接增强角质形成细胞中 TNF 和趋化因子的表达。这些观察结果表明，过量的 IL-1 信号直接激活角质形成细胞产生 TNF 和趋化因子，导致银屑病样皮肤病变的发展，而 Il1rn(-/-) 小鼠中不存在自身免疫。
