Enhancing Antiviral Immunity in the Gastrointestinal Epithelium: The Role of Fibroblast–Endothelium Interaction and Melatonin
The gastrointestinal (GI) tract is a major barrier against pathogens, including viruses. The antiviral responses in the GI epithelium have been broadly investigated, but data on the contribution of the stromal cells remain scarce. Melatonin, widely used to treat insomnia, has recently been proposed...
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2025-06-01
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| author | Milda Šeškutė Goda Laucaitytė Rūta Inčiūraitė Mantas Malinauskas Lina Jankauskaitė |
| author_facet | Milda Šeškutė Goda Laucaitytė Rūta Inčiūraitė Mantas Malinauskas Lina Jankauskaitė |
| author_sort | Milda Šeškutė |
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| description | The gastrointestinal (GI) tract is a major barrier against pathogens, including viruses. The antiviral responses in the GI epithelium have been broadly investigated, but data on the contribution of the stromal cells remain scarce. Melatonin, widely used to treat insomnia, has recently been proposed as an antiviral agent, yet its effect in the GI tract remains poorly understood. We compared the antiviral responses in Caco-2 monocultures and co-cultures with intestinal fibroblasts (HSIFs) and endothelial cells (HUVECs) after stimulation using Poly I:C. We evaluated the apoptosis, proliferation, key antiviral markers (IRF1, IRF3, IFNs, TBK1, STAT3), and mitochondrial and peroxisomal activation with and without melatonin. The Caco-2 cells cultured with the HSIFs and HUVECs demonstrated enhanced proliferation and reduced Poly I:C-induced apoptosis. The co-culture exhibited a more rapid IRF3-IFNλ1 response, higher TBK1 expression, and enhanced peroxisomal activation compared to these properties in the monoculture. Melatonin further reduced apoptosis and modulated organelle-specific antiviral signaling by suppressing peroxisomal activation and promoting mitochondrial activity. Reduced peroxisomal activation was associated with decreased TBK1, IRF3, and IFNλ1 levels and altered STAT3 signaling. These effects were more pronounced when melatonin was applied post-stimulation compared to that under prophylactic use. Fibroblast–endothelial interactions amplify the antiviral responses in the intestinal epithelial cells by activating the TBK1–IRF3–IFNλ1 axis. Melatonin modulates these responses, highlighting its therapeutic potential in viral GI infections. |
| format | Article |
| id | doaj-art-987a039a3d2a4202aa9c517a1355ccb0 |
| institution | Kabale University |
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| language | English |
| publishDate | 2025-06-01 |
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| series | Cells |
| spelling | doaj-art-987a039a3d2a4202aa9c517a1355ccb02025-08-20T03:50:17ZengMDPI AGCells2073-44092025-06-01141399010.3390/cells14130990Enhancing Antiviral Immunity in the Gastrointestinal Epithelium: The Role of Fibroblast–Endothelium Interaction and MelatoninMilda Šeškutė0Goda Laucaitytė1Rūta Inčiūraitė2Mantas Malinauskas3Lina Jankauskaitė4Department of Pediatrics, Lithuanian University of Health Sciences, 44307 Kaunas, LithuaniaDepartment of Pediatrics, Lithuanian University of Health Sciences, 44307 Kaunas, LithuaniaInstitute for Digestive Research, Lithuanian University of Health Sciences, 44307 Kaunas, LithuaniaInstitute of Physiology and Pharmacology, Lithuanian University of Health Sciences, 44307 Kaunas, LithuaniaDepartment of Pediatrics, Lithuanian University of Health Sciences, 44307 Kaunas, LithuaniaThe gastrointestinal (GI) tract is a major barrier against pathogens, including viruses. The antiviral responses in the GI epithelium have been broadly investigated, but data on the contribution of the stromal cells remain scarce. Melatonin, widely used to treat insomnia, has recently been proposed as an antiviral agent, yet its effect in the GI tract remains poorly understood. We compared the antiviral responses in Caco-2 monocultures and co-cultures with intestinal fibroblasts (HSIFs) and endothelial cells (HUVECs) after stimulation using Poly I:C. We evaluated the apoptosis, proliferation, key antiviral markers (IRF1, IRF3, IFNs, TBK1, STAT3), and mitochondrial and peroxisomal activation with and without melatonin. The Caco-2 cells cultured with the HSIFs and HUVECs demonstrated enhanced proliferation and reduced Poly I:C-induced apoptosis. The co-culture exhibited a more rapid IRF3-IFNλ1 response, higher TBK1 expression, and enhanced peroxisomal activation compared to these properties in the monoculture. Melatonin further reduced apoptosis and modulated organelle-specific antiviral signaling by suppressing peroxisomal activation and promoting mitochondrial activity. Reduced peroxisomal activation was associated with decreased TBK1, IRF3, and IFNλ1 levels and altered STAT3 signaling. These effects were more pronounced when melatonin was applied post-stimulation compared to that under prophylactic use. Fibroblast–endothelial interactions amplify the antiviral responses in the intestinal epithelial cells by activating the TBK1–IRF3–IFNλ1 axis. Melatonin modulates these responses, highlighting its therapeutic potential in viral GI infections.https://www.mdpi.com/2073-4409/14/13/990gastrointestinal co-culture modelantiviralmelatoninperoxisomesIFNλ1IRF3 |
| spellingShingle | Milda Šeškutė Goda Laucaitytė Rūta Inčiūraitė Mantas Malinauskas Lina Jankauskaitė Enhancing Antiviral Immunity in the Gastrointestinal Epithelium: The Role of Fibroblast–Endothelium Interaction and Melatonin Cells gastrointestinal co-culture model antiviral melatonin peroxisomes IFNλ1 IRF3 |
| title | Enhancing Antiviral Immunity in the Gastrointestinal Epithelium: The Role of Fibroblast–Endothelium Interaction and Melatonin |
| title_full | Enhancing Antiviral Immunity in the Gastrointestinal Epithelium: The Role of Fibroblast–Endothelium Interaction and Melatonin |
| title_fullStr | Enhancing Antiviral Immunity in the Gastrointestinal Epithelium: The Role of Fibroblast–Endothelium Interaction and Melatonin |
| title_full_unstemmed | Enhancing Antiviral Immunity in the Gastrointestinal Epithelium: The Role of Fibroblast–Endothelium Interaction and Melatonin |
| title_short | Enhancing Antiviral Immunity in the Gastrointestinal Epithelium: The Role of Fibroblast–Endothelium Interaction and Melatonin |
| title_sort | enhancing antiviral immunity in the gastrointestinal epithelium the role of fibroblast endothelium interaction and melatonin |
| topic | gastrointestinal co-culture model antiviral melatonin peroxisomes IFNλ1 IRF3 |
| url | https://www.mdpi.com/2073-4409/14/13/990 |
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