Urocortin 3 expression at baseline and during inflammation in the colon: corticotropin releasing factor receptors cross-talk.
Urocortin 3 expression at baseline and during inflammation in the colon: corticotropin releasing factor receptors cross-talk.
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DOI：
10.1016/j.peptides.2014.01.007
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发表时间：
2014-04
期刊：
影响因子：
3
通讯作者：
Bhargava A
中科院分区：
文献类型：
--
作者：
Mahajan S;Liao M;Barkan P;Takahashi K;Bhargava A
Urocortins(Ucn1-3)是促肾上腺皮质激素释放因子(CRF)家族神经肽中的一员，正逐渐成为一种有效的免疫调节剂。在炎症过程中，Ucn1和Ucn2有局部的细胞表达，但Ucn3没有表达。在这里，我们研究了Ucn3在克罗恩结肠炎大鼠模型中的作用，以及CRF受体(CRF1和CRF2)在基础状态和炎症过程中调节Ucn3表达的相对作用。幼稚大鼠胃肠道广泛表达Ucn3mRNA和Ucn3肽。UCN3免疫反应见于上皮细胞和肌间神经元。在结肠炎的第1天，Ucn3的mRNA水平下降了80%，到第9天仍未恢复到基线水平。接下来，我们确定了Ucn3在结肠炎期间的促炎或抗炎作用。令人惊讶的是，与观察到的UCN1的抗炎作用不同，外源性UCN3没有改变结肠炎期间的组织病理结果，也没有改变促炎细胞因子IL-6和肿瘤坏死因子-α的水平。在基线时，CRF1的结肠特异性敲除，而不是CRF2，使Ucn3mRNA降低78%，而在结肠炎期间，CRF1敲除后Ucn3mRNA水平升高。在培养的细胞中，与单独表达CRF2的细胞相比，共表达CRF1+CRF2使Ucn3刺激的细胞内钙峰值降低了48%。结肠炎时p38蛋白的磷酸化水平增加250%，Ucn3治疗后p38蛋白的磷酸化水平明显减弱。因此，我们的结果表明，CRF受体的平衡和协调表达是在基线和炎症期间适当调节Ucn3所必需的。
Urocortins (Ucn1–3), members of the corticotropin-releasing factor (CRF) family of neuropeptides, are emerging as potent immunomodulators. Localized, cellular expression of Ucn1 and Ucn2, but not Ucn3, has been demonstrated during inflammation. Here, we investigated the role of Ucn3 in a rat model of Crohn’s colitis and the relative contribution of CRF receptors (CRF1 and CRF2) in regulating Ucn3 expression at baseline and during inflammation. Ucn3 mRNA and peptide were ubiquitously expressed throughout the GI tract in naïve rats. Ucn3 immunoreactivity was seen in epithelial cells and myenteric neurons. On day 1 of colitis, Ucn3 mRNA levels decreased by 80% and did not recover to baseline even by day 9. Next, we ascertained pro- or anti-inflammatory actions of Ucn3 during colitis. Surprisingly, unlike observed anti-inflammatory actions of Ucn1, exogenous Ucn3 did not alter histopathological outcomes during colitis and neither did it alter levels of pro-inflammatory cytokines IL-6 and TNF-α. At baseline, colon-specific knockdown of CRF1, but not CRF2 decreased Ucn3 mRNA by 78%, whereas during colitis, Ucn3 mRNA levels increased after CRF1 knockdown. In cultured cells, co-expression of CRF1 + CRF2 attenuated Ucn3-stimulated intracellular Ca2+ peak by 48% as compared to cells expressing CRF2 alone. Phosphorylation of p38 kinase increased by 250% during colitis and was significantly attenuated after Ucn3 administration. Thus, our results suggest that a balanced and coordinated expression of CRF receptors is required for proper regulation of Ucn3 at baseline and during inflammation.
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影响因子：
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作者：
Jonak, Constanze;Mildner, Michael;Trautinger, Franz
通讯作者：
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影响因子：
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DOI：
10.1152/ajpgi.00464.2006
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