Departments of General-, Visceral-, Vascular and Pediatric Surgery PathologyUniversity of Wuerzburg Hospital, Wuerzburg, Germany.
Colorectal Dis. 2012 Oct;14(10):1276-86. doi: 10.1111/j.1463-1318.2012.02967.x.
Immunosuppression and steroid medication have been identified as risk factors for complicated sigmoid diverticulitis. The underlying molecular mechanisms have not yet been elucidated. We hypothesized that glucocorticoid-induced tumour necrosis factor receptor (GITR) and matrix metalloproteinase-9 (MMP-9) might play a role.
GITR and MMP-9 were analysed at protein [immunohistochemistry/immunofluorescence (IF)] and messenger RNA level (real-time polymerase chain reaction) in surgical specimens with complicated and non-complicated diverticulitis (n=101). IF double staining and regression analysis were performed for both markers. GITR expression was correlated with clinical data and its usefulness as a diagnostic test was investigated.
High GITR expression (≥41%) was observed in the inflammatory infiltrate in complicated diverticulitis, in contrast to non-complicated diverticulitis where GITR expression was low (P<0.001). High GITR expression was significantly associated with steroid use and pulmonary diseases (both P<0.001). MMP-9 expression correlated with GITR expression (R(2) =0.7268, P<0.0001, r=0.85) as demonstrated with IF double-staining experiments. Co-labelling of GITR with CD68, but not CD15, suggested that GITR-expressing cells in diverticulitis are macrophages. GITR expression was superior to C-reactive protein (CRP), white cell count and temperature in distinguishing complicated and non-complicated diverticulitis.
Our results suggest that GITR expression in inflammatory cells might potentially indicate a molecular link between steroid use and complicated forms of acute sigmoid diverticulitis. Increased MMP-9 expression by GITR signalling might explain the morphological changes in the colonic wall of perforated and phlegmonous diverticulitis. Analysis of soluble GITR might be a promising strategy for future research.
免疫抑制和类固醇药物已被确定为复杂乙状结肠憩室炎的危险因素。但其潜在的分子机制尚未阐明。我们假设糖皮质激素诱导的肿瘤坏死因子受体（GITR）和基质金属蛋白酶-9（MMP-9）可能发挥作用。
对 101 例复杂和非复杂憩室炎手术标本进行了 GITR 和 MMP-9 的蛋白[免疫组化/免疫荧光（IF）]和信使 RNA 水平（实时聚合酶链反应）分析。对这两种标志物进行了 IF 双重染色和回归分析。分析了 GITR 表达与临床数据的相关性，并探讨了其作为诊断试验的有用性。
在复杂憩室炎中，炎症浸润中观察到高 GITR 表达（≥41%），而非复杂憩室炎中 GITR 表达水平较低（P<0.001）。高 GITR 表达与类固醇使用和肺部疾病显著相关（均 P<0.001）。IF 双重染色实验表明，MMP-9 表达与 GITR 表达相关（R²=0.7268，P<0.0001，r=0.85）。GITR 表达与 CD68 共标记，但与 CD15 不共标记，表明憩室炎中 GITR 表达的细胞为巨噬细胞。GITR 表达在区分复杂和非复杂憩室炎方面优于 C 反应蛋白（CRP）、白细胞计数和体温。
我们的研究结果表明，炎症细胞中 GITR 的表达可能潜在地表明类固醇使用与急性乙状结肠憩室炎复杂形式之间的分子联系。GITR 信号增加 MMP-9 的表达可能解释了穿孔和脓性憩室炎结肠壁的形态学变化。分析可溶性 GITR 可能是未来研究的一个有前途的策略。
