Anti-Inflammatory Effects of Synthetic Peptides Based on Glucocorticoid-Induced Leucine Zipper (GILZ) Protein for the Treatment of Inflammatory Bowel Diseases (IBDs)
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 a...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-09-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/18/2294 |
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| author | Musetta Paglialunga Sara Flamini Raffaele Contini Marta Febo Erika Ricci Simona Ronchetti Oxana Bereshchenko Graziella Migliorati Carlo Riccardi Stefano Bruscoli |
| author_facet | Musetta Paglialunga Sara Flamini Raffaele Contini Marta Febo Erika Ricci Simona Ronchetti Oxana Bereshchenko Graziella Migliorati Carlo Riccardi Stefano Bruscoli |
| author_sort | Musetta Paglialunga |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T22:56:40Z |
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| id | doaj.art-d48756392fb04ff4a60ca02fd9e467df |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T22:56:40Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-d48756392fb04ff4a60ca02fd9e467df2023-11-19T10:00:01ZengMDPI AGCells2073-44092023-09-011218229410.3390/cells12182294Anti-Inflammatory Effects of Synthetic Peptides Based on Glucocorticoid-Induced Leucine Zipper (GILZ) Protein for the Treatment of Inflammatory Bowel Diseases (IBDs)Musetta Paglialunga0Sara Flamini1Raffaele Contini2Marta Febo3Erika Ricci4Simona Ronchetti5Oxana Bereshchenko6Graziella Migliorati7Carlo Riccardi8Stefano Bruscoli9Department of Medicine and Surgery, Section of Pharmacology, University of Perugia, 06132 Perugia, ItalyDepartment of Medicine and Surgery, Section of Pharmacology, University of Perugia, 06132 Perugia, ItalyDepartment of Medicine and Surgery, Section of Pharmacology, University of Perugia, 06132 Perugia, ItalyDepartment of Medicine and Surgery, Section of Pharmacology, University of Perugia, 06132 Perugia, ItalyDepartment of Medicine and Surgery, Section of Pharmacology, University of Perugia, 06132 Perugia, ItalyDepartment of Medicine and Surgery, Section of Pharmacology, University of Perugia, 06132 Perugia, ItalyDepartment of Philosophy, Social Sciences and Education, University of Perugia, 06123 Perugia, ItalyDepartment of Medicine and Surgery, Section of Pharmacology, University of Perugia, 06132 Perugia, ItalyDepartment of Medicine and Surgery, Section of Pharmacology, University of Perugia, 06132 Perugia, ItalyDepartment of Medicine and Surgery, Section of Pharmacology, University of Perugia, 06132 Perugia, ItalyGlucocorticoids (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.https://www.mdpi.com/2073-4409/12/18/2294glucocorticoidsGILZinflammationNF-κBIBDs |
| spellingShingle | Musetta Paglialunga Sara Flamini Raffaele Contini Marta Febo Erika Ricci Simona Ronchetti Oxana Bereshchenko Graziella Migliorati Carlo Riccardi Stefano Bruscoli Anti-Inflammatory Effects of Synthetic Peptides Based on Glucocorticoid-Induced Leucine Zipper (GILZ) Protein for the Treatment of Inflammatory Bowel Diseases (IBDs) Cells glucocorticoids GILZ inflammation NF-κB IBDs |
| title | Anti-Inflammatory Effects of Synthetic Peptides Based on Glucocorticoid-Induced Leucine Zipper (GILZ) Protein for the Treatment of Inflammatory Bowel Diseases (IBDs) |
| title_full | Anti-Inflammatory Effects of Synthetic Peptides Based on Glucocorticoid-Induced Leucine Zipper (GILZ) Protein for the Treatment of Inflammatory Bowel Diseases (IBDs) |
| title_fullStr | Anti-Inflammatory Effects of Synthetic Peptides Based on Glucocorticoid-Induced Leucine Zipper (GILZ) Protein for the Treatment of Inflammatory Bowel Diseases (IBDs) |
| title_full_unstemmed | Anti-Inflammatory Effects of Synthetic Peptides Based on Glucocorticoid-Induced Leucine Zipper (GILZ) Protein for the Treatment of Inflammatory Bowel Diseases (IBDs) |
| title_short | Anti-Inflammatory Effects of Synthetic Peptides Based on Glucocorticoid-Induced Leucine Zipper (GILZ) Protein for the Treatment of Inflammatory Bowel Diseases (IBDs) |
| title_sort | anti inflammatory effects of synthetic peptides based on glucocorticoid induced leucine zipper gilz protein for the treatment of inflammatory bowel diseases ibds |
| topic | glucocorticoids GILZ inflammation NF-κB IBDs |
| url | https://www.mdpi.com/2073-4409/12/18/2294 |
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