Arranz Alicia, Juarranz Yasmina, Leceta Javier, Gomariz Rosa P, Martínez Carmen
Department of Cell Biology, Faculty of Biology, Complutense University, 28040 Madrid, Spain.
Peptides. 2008 Jun;29(6):948-56. doi: 10.1016/j.peptides.2008.01.019. Epub 2008 Feb 7.
Crohn's disease (CD) is a chronic intestinal inflammatory pathology, which develops as a result of innate immune signals, such as the activation of Toll-like receptors (TLRs), and adaptive immune signals, including Th1 cytokine release. We have recently demonstrated in TNBS-induced colitis, a murine model of CD, that VIP plays a homeostatic role, by reducing TNBS-induced TLR2 and TLR4 expression to control levels. The purpose of this paper is to elucidate for the first time, the physiological relevance of VIP specific control of innate and adaptive immune responses through TLR2 and TLR4 ligands. In addition, we investigated the effect of VIP on regulatory activity of T regulatory (Treg) cells in the TNBS-colitis model. First, we found that VIP downregulated the inflammatory response elicited in mesenteric lymph node cell cultures by treatment with the TLR2 ligand Pam3Cys, or the TLR4 ligand lipopolysaccharide (LPS), reducing the production of the chemokine CXCL1. Also, treatment with VIP impaired the induction of Th1 responses by decreasing p70 interleukin (IL)-12 and interferon gamma (IFN-gamma) levels after TLR2/TLR4 stimulation in culture. Besides, VIP treatment restored in vivo the numbers of TLR2 and TLR4 positive CD4+CD25+ T lymphocytes, augmented by TNBS administration, and increased the expression of molecules involved in regulatory T cell function, such as Foxp3 and TGF-beta. In conclusion, the ability of VIP to down-regulate uncontrolled inflammation by targeting TLR-mediated responses and regulatory T cell activity could be used as a new alternative therapy for intestinal inflammatory/autoimmune disorders.
克罗恩病（CD）是一种慢性肠道炎症性病变，其由先天性免疫信号（如Toll样受体（TLR）的激活）和适应性免疫信号（包括Th1细胞因子释放）引发。我们最近在TNBS诱导的结肠炎（一种CD的小鼠模型）中证明，VIP通过将TNBS诱导的TLR2和TLR4表达降低至对照水平而发挥稳态作用。本文的目的是首次阐明VIP通过TLR2和TLR4配体对先天性和适应性免疫反应进行特异性控制的生理相关性。此外，我们在TNBS结肠炎模型中研究了VIP对调节性T（Treg）细胞调节活性的影响。首先，我们发现VIP下调了用TLR2配体Pam3Cys或TLR4配体脂多糖（LPS）处理后在肠系膜淋巴结细胞培养物中引发的炎症反应，减少了趋化因子CXCL1的产生。此外，VIP处理通过在培养物中TLR2/TLR4刺激后降低p70白细胞介素（IL）-12和干扰素γ（IFN-γ）水平而损害了Th1反应的诱导。此外，VIP处理在体内恢复了由TNBS给药增加的TLR2和TLR4阳性CD4 + CD25 + T淋巴细胞数量，并增加了参与调节性T细胞功能的分子（如Foxp3和TGF-β）的表达。总之，VIP通过靶向TLR介导的反应和调节性T细胞活性来下调不受控制的炎症的能力可作为肠道炎症/自身免疫性疾病的一种新的替代疗法。
