Long-term exposure of the HT-29 human intestinal epithelial cell line to TNF causes sustained up-regulation of the polymeric Ig receptor and proinflammatory genes through transcriptional and posttranscriptional mechanisms
Long-term exposure of the HT-29 human intestinal epithelial cell line to TNF causes sustained up-regulation of the polymeric Ig receptor and proinflammatory genes through transcriptional and posttranscriptional mechanisms
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DOI：
10.4049/jimmunol.174.11.7278
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发表时间：
2005-06-01
影响因子：
4.4
通讯作者：
Kaetzel, CS
中科院分区：
文献类型：
--
作者：
Bruno, MEC;Kaetzel, CS
伊加Ab穿过肠上皮细胞进入肠道分泌物的转运由多聚IG受体（pIgR）介导。细胞因子TNF在引发和放大炎症反应中起核心作用，并且与炎症性肠病的发病机制有关。肠上皮细胞系急性暴露于TNF已显示上调编码pIgR和许多促炎因子的基因的转录，但尚未研究慢性暴露于TNF的影响。我们发现，HT-29人结肠癌细胞暴露于TNF达20天降低了细胞增殖率，但没有引起大体形态学变化。编码pIgR和几种促炎基因的mRNA表达急剧增加，然后减少，但在整个实验中仍高于对照水平。转录因子IFN调节因子-1和NF-κ B B的ReIB亚基的表达增加导致基因表达的变化。HT-29细胞激活内源性TNF基因响应TNF治疗，但TNF的生产水平不足以维持pIgR和促炎基因表达后撤出外源性TNF。慢性暴露于TNF导致pIgR mRNA稳定性显著增加，TNF mRNA稳定性小幅但显著降低，但IL-8、c-Myc和GAPDH的半衰期无变化。总之，我们观察到急性与慢性暴露于TNF对基因表达的不同影响，并发现了pIgR表达的转录和转录后调节的证据。
Transport of IgA Abs across intestinal epithelial cells into gut secretions is mediated by the polymeric Ig receptor (pIgR). The cytokine TNF plays a central role in initiating and amplifying inflammatory reactions, and is implicated in the pathogenesis of inflammatory bowel diseases. Acute exposure of intestinal epithelial cell lines to TNF has been shown to up-regulate transcription of genes encoding pIgR and a number of proinflammatory factors, but the effects of chronic exposure to TNF have not been studied. We found that exposure of HT-29 human colon carcinoma cells to TNF for up to 20 days reduced the rate of cell proliferation, but did not cause gross morphological changes. Expression of mRNA encoding pIgR and several proinflammatory genes increased acutely, and then diminished but remained elevated above control levels throughout the experiment. Changes in gene expression were paralleled by increased expression of the transcription factors IFN regulatory.factor-1 and the ReIB subunit of NF-kappa B. HT-29 cells activated the endogenous TNF gene in response to TNF treatment, but the level of TNF production was insufficient to maintain pIgR and proinflammatory gene expression after withdrawal of exogenous TNF. Chronic exposure to TNF caused a marked increase in pIgR mRNA stability and a small but significant decrease in TNF mRNA stability, but no change in the half-lives of IL-8, c-Myc, and GAPDH. In summary, we observed different effects of acute vs chronic exposure to TNF on gene expression, and found evidence for transcriptional and posttranscriptional regulation of expression of the pIgR.