Fleischmajer R, Kuroda K, Hazan R, Gordon R E, Lebwohl M G, Sapadin A N, Unda F, Iehara N, Yamada Y
Department of Dermatology, Mount Sinai Medical Center, New York, NY 10029, USA.
J Invest Dermatol. 2000 Nov;115(5):771-7. doi: 10.1046/j.1523-1747.2000.00138.x.
Psoriasis is most probably an inherited disease characterized by cell proliferation, angiogenesis, and an inflammatory process. The pathophysiology remains unknown, although an alteration in cell-cell and cell-matrix adhesion versus an autoimmune process has been proposed as the primary defect. Here, we show evidence of a new mechanism involving basement membrane alterations accompanied by keratinocyte overexpression of matrix metalloproteinase (MMP) 2 and tissue inhibitor of MMP-2 (TIMP-2) in both uninvolved and involved psoriatic skin. Immunocytochemistry with antibodies against collagen IV (alpha1, alpha2 chains) and laminins (alpha2, alpha5, beta1, gamma1 chains) revealed gaps, folding, and reduplication of the epidermo-dermal basement membrane. There was overexpression of MMP-2 in the cytoplasm of suprabasal keratinocytes. Gelatin zymography revealed pro-MMP-2 and its activated form, a-MMP-2, in both uninvolved and involved psoriatic skin, whereas pro-MMP-9 was only present in involved skin. TIMP-2 was expressed at the cell surface of psoriatic involved suprabasal keratinocytes whereas it was restricted to basal keratinocytes in uninvolved areas. Western blots showed a marked increase in a-MMP-2 and TIMP-2 in uninvolved and involved psoriatic skin although it was more pronounced in the latter. MT1-MP, known to activate pro-MMP-2, was increased in involved areas. In situ hybridization revealed strong signals of MMP-2 mRNA in both uninvolved and involved psoriatic epidermis. The overexpression of MMP-2 in uninvolved and involved psoriatic epidermis supports the concept that the primary alteration may reside in the keratinocyte. In addition, the presence of the activated form of MMP-2 could be responsible for cell-cell and cell-matrix changes noted in psoriatic epidermis.
银屑病很可能是一种遗传性疾病，其特征为细胞增殖、血管生成和炎症过程。尽管有人提出细胞间和细胞与基质黏附的改变相对于自身免疫过程是主要缺陷，但病理生理学仍不清楚。在此，我们展示了一种新机制的证据，该机制涉及在未受累和受累的银屑病皮肤中基底膜改变，同时伴有角质形成细胞基质金属蛋白酶（MMP）2和MMP-2组织抑制剂（TIMP-2）的过表达。用抗IV型胶原（α1、α2链）和层粘连蛋白（α2、α5、β1、γ1链）抗体进行免疫细胞化学检测发现，表皮-真皮基底膜存在间隙、折叠和重复。基底上层角质形成细胞的细胞质中MMP-2过表达。明胶酶谱分析显示，在未受累和受累的银屑病皮肤中均存在前MMP-2及其活化形式α-MMP-2，而前MMP-9仅存在于受累皮肤中。TIMP-2在受累的银屑病基底上层角质形成细胞的细胞表面表达，而在未受累区域则局限于基底角质形成细胞。蛋白质免疫印迹显示，在未受累和受累的银屑病皮肤中，α-MMP-2和TIMP-2均显著增加，尽管在后者中更为明显。已知可激活前MMP-2的MT1-MP在受累区域增加。原位杂交显示，在未受累和受累的银屑病表皮中均有强烈的MMP-2 mRNA信号。未受累和受累的银屑病表皮中MMP-2的过表达支持了主要改变可能存在于角质形成细胞中的观点。此外，MMP-2活化形式的存在可能是银屑病表皮中细胞间和细胞与基质变化的原因。
