Paglialunga Musetta, Flamini Sara, Contini Raffaele, Febo Marta, Ricci Erika, Ronchetti Simona, Bereshchenko Oxana, Migliorati Graziella, Riccardi Carlo, Bruscoli Stefano
Department of Medicine and Surgery, Section of Pharmacology, University of Perugia, 06132 Perugia, Italy.
Department of Philosophy, Social Sciences and Education, University of Perugia, 06123 Perugia, Italy.
Cells. 2023 Sep 16;12(18):2294. doi: 10.3390/cells12182294.
Glucocorticoids (GCs) are commonly used to treat autoimmune and inflammatory diseases, but their clinical effects and long-term use can lead to serious side effects. New drugs that can replace GCs are needed. Glucocorticoid-induced leucine zipper (GILZ) is induced by GCs and mediates many of their anti-inflammatory effects, such as inhibiting the pro-inflammatory molecule NF-κB. The GILZ C-terminal domain (PER region) is responsible for GILZ/p65NF-κB interaction and consequent inhibition of its transcriptional activity. A set of five short peptides spanning different parts of the PER region of GILZ protein was designed, and their anti-inflammatory activity was tested, both in vitro and in vivo. We tested the biological activity of GILZ peptides in human lymphocytic and monocytic cell lines to evaluate their inhibitory effect on the NF-κB-dependent expression of pro-inflammatory cytokines. Among the tested peptides, the peptide named PEP-1 demonstrated the highest efficacy in inhibiting cell activation in vitro. Subsequently, PEP-1 was further evaluated in two in vivo experimental colitis models (chemically induced by DNBS administration and spontaneous colitis induced in IL-10 knock-out (KO) mice (to assess its effectiveness in counteracting inflammation. Results show that PEP-1 reduced disease severity in both colitis models associated with reduced NF-κB pro-inflammatory activity in colon lamina propria lymphocytes. This study explored GILZ-based 'small peptides' potential efficacy in decreasing lymphocyte activation and inflammation associated with experimental inflammatory bowel diseases (IBDs). Small peptides have several advantages over the entire protein, including higher selectivity, better stability, and bioavailability profile, and are easy to synthesize and cost-effective. Thus, identifying active GILZ peptides could represent a new class of drugs for treating IBD patients.
糖皮质激素（GCs）常用于治疗自身免疫性疾病和炎症性疾病，但其临床效果和长期使用会导致严重的副作用。因此，需要能够替代GCs的新药。糖皮质激素诱导亮氨酸拉链蛋白（GILZ）由GCs诱导产生，并介导其许多抗炎作用，如抑制促炎分子NF-κB。GILZ的C末端结构域（PER区域）负责GILZ与p65NF-κB的相互作用，从而抑制其转录活性。我们设计了一组跨越GILZ蛋白PER区域不同部分的五个短肽，并在体外和体内测试了它们的抗炎活性。我们在人淋巴细胞和单核细胞系中测试了GILZ肽的生物学活性，以评估它们对促炎细胞因子NF-κB依赖性表达的抑制作用。在测试的肽中，名为PEP-1的肽在体外抑制细胞活化方面表现出最高的功效。随后，在两种体内实验性结肠炎模型中对PEP-1进行了进一步评估（一种是通过给予二硝基苯磺酸（DNBS）化学诱导的，另一种是在白细胞介素-10基因敲除（KO）小鼠中诱导的自发性结肠炎，以评估其对抗炎症的有效性）。结果表明，在两个结肠炎模型中，PEP-1均降低了疾病严重程度，同时结肠固有层淋巴细胞中NF-κB的促炎活性也降低。本研究探讨了基于GILZ的“小肽”在降低与实验性炎症性肠病（IBD）相关的淋巴细胞活化和炎症方面的潜在功效。与完整蛋白质相比，小肽具有几个优点，包括更高的选择性、更好的稳定性和生物利用度，并且易于合成且成本效益高。因此，鉴定具有活性的GILZ肽可能代表一类治疗IBD患者的新型药物。
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