Laboratory of Pediatrics, Rotterdam, The Netherlands.
Am J Physiol Gastrointest Liver Physiol. 2011 Oct;301(4):G667-78. doi: 10.1152/ajpgi.00199.2010. Epub 2011 Jun 23.
The mucin Muc2 is the structural component of the colonic mucus layer. Adult Muc2 knockout (Muc2(-/-)) mice suffer from severe colitis. We hypothesized that Muc2 deficiency induces inflammation before weaning of mother's milk [postnatal day (P) 14] with aggravation of colitis after weaning (P28). Muc2(-/-) and wild-type mice were killed at embryonic day 18.5 and P1.5, P7.5, P14, P21, and P28. Colonic morphology, influx of T cells, and goblet cell-specific protein expression was investigated by (immuno)histochemistry. Cytokine and Toll-like receptor (TLR) profiles in the colon were analyzed by quantitative RT-PCR. Muc2(-/-) mice showed an increased and persistent influx of Cd3ε-positive T cells in the colonic mucosa as of P1.5. This was accompanied by mucosal damage at P28 in the distal colon but not in the proximal colon. At P14, the proinflammatory immune response [i.e., increased interleukin (IL)-12 p35, IL-12 p40, and tumor necrosis factor-α, expression] in the distal colon of Muc2(-/-) mice presented with an immune suppressive response [i.e., increased Foxp3, transforming growth factor (TGF)-β1, IL-10, and Ebi3 expression]. In contrast, at P28, a proinflammatory response remained in the distal colon, whereas the immune suppressive response (i.e., Foxp3 and TGF-β1 expression) declined. The proximal colon of Muc2(-/-) mice did not show morphological damage and was dominated by an immune suppressive response at P14 and P28. Interestingly, changes in expression of TLRs and TLR-related molecules were observed in the distal colon at P14 and P28 and in the proximal colon only at P28. Colitis in Muc2(-/-) mice is limited before weaning by immune suppressive responses and exacerbates in the distal colon after weaning because of the decline in the immune suppressive response.
黏蛋白 Muc2 是结肠黏液层的结构成分。成年 Muc2 敲除（Muc2(-/-)）小鼠患有严重的结肠炎。我们假设 Muc2 缺乏会在断奶前（出生后第 14 天[P14]）引起炎症，并在断奶后（P28）加重结肠炎。Muc2(-/-)和野生型小鼠分别在胚胎第 18.5 天和 P1.5、P7.5、P14、P21 和 P28 处死。通过（免疫）组织化学方法研究结肠形态、T 细胞浸润和杯状细胞特异性蛋白表达。通过定量 RT-PCR 分析结肠中的细胞因子和 Toll 样受体（TLR）谱。从 P1.5 开始，Muc2(-/-)小鼠的结肠黏膜中就出现了持续增加的 Cd3ε 阳性 T 细胞浸润。这伴随着 P28 时远端结肠的黏膜损伤，但在近端结肠则没有。在 P14 时，Muc2(-/-)小鼠的远端结肠中的促炎免疫反应（即增加白细胞介素（IL）-12 p35、IL-12 p40 和肿瘤坏死因子-α表达）表现出免疫抑制反应（即增加 Foxp3、转化生长因子（TGF）-β1、IL-10 和 Ebi3 表达）。相比之下，在 P28 时，远端结肠仍存在促炎反应，而免疫抑制反应（即 Foxp3 和 TGF-β1 表达）则下降。Muc2(-/-)小鼠的近端结肠在 P14 和 P28 时没有形态损伤，并且以免疫抑制反应为主，而在 P28 时仅观察到 TLRs 和 TLR 相关分子的表达变化。在 P14 和 P28 时，远端结肠和仅在 P28 时，近端结肠都观察到了这种变化。Muc2(-/-)小鼠的结肠炎在断奶前受到免疫抑制反应的限制，在断奶后由于免疫抑制反应的减弱，在远端结肠加重。
