Rimondi Erika, Secchiero Paola, Quaroni Andrea, Zerbinati Carlotta, Capitani Silvano, Zauli Giorgio
Department of Morphology and Embryology, University of Ferrara, Via Fossato di Mortara, Ferrara, Italy.
J Cell Physiol. 2006 Mar;206(3):647-54. doi: 10.1002/jcp.20512.
Despite the fact that tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) and its receptors (TRAIL-Rs) are expressed in intestinal mucosa, little is known about the biological role of this system in intestinal cell physiology. The expression of surface TRAIL and TRAIL-R1, -R2, -R3, -R4 were examined by flow cytometry in the immortalized human cell line tsFHI under culture conditions promoting growth or growth arrest and expression of differentiated traits. A progressive increase of surface TRAIL expression paralleled tsFHI differentiation, consistently with immunohistochemistry analysis showing an increase of TRAIL immunostaining along the crypt-villus axis in normal jejuneal mucosa. In spite of the presence of TRAIL-R1 and TRAIL-R2 "death receptors," recombinant TRAIL was not cytotoxic for tsFHI cells. Exposure of tsFHI to recombinant TRAIL rather increased/anticipated the expression levels of the cyclin-dependent kinase inhibitors p21 and p27, which mediate the induction of growth arrest and the stabilization of differentiated traits, respectively, as well as of the canonical differentiation marker DPPIV. The differentiation inducing activity of TRAIL was abolished by pre-incubation with a Fc-TRAIL-R2 chimera. On the other hand, TRAIL did not significantly modulate the levels of osteoprotegerin (OPG), CXCL8/IL-8, CXCL9/MIG, and CXCL10/IP10 spontaneously released or induced by inflammatory cytokines. Taken together, these data suggest that TRAIL might act as a paracrine trophic cytokine on intestinal epithelium, promoting intestinal cell differentiation.
尽管肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）及其受体（TRAIL-Rs）在肠黏膜中表达，但关于该系统在肠道细胞生理学中的生物学作用知之甚少。在促进生长或生长停滞以及分化特征表达的培养条件下，通过流式细胞术检测永生化人细胞系tsFHI表面TRAIL和TRAIL-R1、-R2、-R3、-R4的表达。表面TRAIL表达的逐渐增加与tsFHI分化平行，这与免疫组织化学分析一致，后者显示正常空肠黏膜中沿隐窝-绒毛轴TRAIL免疫染色增加。尽管存在TRAIL-R1和TRAIL-R2“死亡受体”，重组TRAIL对tsFHI细胞没有细胞毒性。将tsFHI暴露于重组TRAIL反而增加/提前了细胞周期蛋白依赖性激酶抑制剂p21和p27的表达水平，它们分别介导生长停滞的诱导和分化特征的稳定，以及经典分化标志物二肽基肽酶IV（DPPIV）的表达。用Fc-TRAIL-R2嵌合体预孵育可消除TRAIL的分化诱导活性。另一方面，TRAIL并未显著调节由炎性细胞因子自发释放或诱导释放的骨保护素（OPG）、CXCL8/IL-8、CXCL9/MIG和CXCL10/IP10的水平。综上所述，这些数据表明TRAIL可能作为肠道上皮的旁分泌营养细胞因子，促进肠道细胞分化。
