Luo C, Laine V J O, Ylinen L, Teros T, Mäkinen M, Ristimäki A, Simell O
The Juvenile Diabetes Research Foundation Center for Prevention of Type 1 Diabetes in Finland, University of Turku, Turku, Finland.
Acta Physiol Scand. 2002 Mar;174(3):265-74. doi: 10.1046/j.1365-201x.2002.00941.x.
Cyclooxygenase, the rate-limiting enzyme in prostaglandin synthesis, is expressed in constitutive (COX-1) and inducible (COX-2) isoforms. The COX-2 has been proposed to be involved in development of autoimmune type 1 diabetes (T1D). We examined COX-2 expression in the gut-associated lymphoid tissue (GALT), and found COX-2 was strongly expressed in goblet cells of non-obese diabetic (NOD) mice at the apical villi at the age of 2.5 weeks, clearly before the onset of insulitis, while the expression in the control BALB/c mice was weak or absent at all ages (P < 0.001). Lipopolysaccharide (LPS) given intraperitoneally slightly increased COX-2 expression in the goblet cells and epithelium of both NOD and BALB/c mice. High-resolution confocal microscopy showed that the surroundings of the goblet cells contained no COX-2, implying that the enzyme is synthesized by the goblet cells. The COX-2 is secreted from goblet cells into the intestinal lumen along with mucins. The COX-2 concentration in the goblet cell of BALB/c and especially of NOD mice was markedly higher than that in the intraepithelial lymphocytes or lamina propria macrophages. High mucin COX-2 from goblet cells may increase luminal prostaglandin synthesis, alter epithelial permeability, modulate intestinal immune responses and modify functional properties of the lymphocytes in the GALT, which all may be important for the initiation of the autoimmune phenomenon in the NOD mice.
环氧化酶是前列腺素合成中的限速酶，以组成型（COX-1）和诱导型（COX-2）同工型表达。有人提出COX-2参与自身免疫性1型糖尿病（T1D）的发生发展。我们检测了肠道相关淋巴组织（GALT）中COX-2的表达，发现2.5周龄的非肥胖糖尿病（NOD）小鼠顶端绒毛的杯状细胞中COX-2强烈表达，明显早于胰岛炎的发生，而对照BALB/c小鼠在所有年龄段的表达均较弱或无表达（P<0.001）。腹腔注射脂多糖（LPS）可使NOD和BALB/c小鼠杯状细胞和上皮细胞中的COX-2表达略有增加。高分辨率共聚焦显微镜显示杯状细胞周围不含COX-2，这意味着该酶是由杯状细胞合成的。COX-2与粘蛋白一起从杯状细胞分泌到肠腔中。BALB/c小鼠尤其是NOD小鼠杯状细胞中的COX-2浓度明显高于上皮内淋巴细胞或固有层巨噬细胞中的浓度。杯状细胞中高含量的粘蛋白COX-2可能会增加肠腔前列腺素的合成，改变上皮通透性，调节肠道免疫反应并改变GALT中淋巴细胞的功能特性，所有这些对于NOD小鼠自身免疫现象的启动可能都很重要。
