Butyrate Prevents Induction of CXCL10 and Non-Canonical IRF9 Expression by Activated Human Intestinal Epithelial Cells via HDAC Inhibition
Non-communicable diseases are increasing and have an underlying low-grade inflammation in common, which may affect gut health. To maintain intestinal homeostasis, unwanted epithelial activation needs to be avoided. This study compared the efficacy of butyrate, propionate and acetate to suppress IFN-...
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| Format: | Article |
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MDPI AG
2022-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/7/3980 |
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| author | Sandra G. P. J. Korsten Laura Peracic Luka M. B. van Groeningen Mara A. P. Diks Herman Vromans Johan Garssen Linette E. M. Willemsen |
| author_facet | Sandra G. P. J. Korsten Laura Peracic Luka M. B. van Groeningen Mara A. P. Diks Herman Vromans Johan Garssen Linette E. M. Willemsen |
| author_sort | Sandra G. P. J. Korsten |
| collection | DOAJ |
| description | Non-communicable diseases are increasing and have an underlying low-grade inflammation in common, which may affect gut health. To maintain intestinal homeostasis, unwanted epithelial activation needs to be avoided. This study compared the efficacy of butyrate, propionate and acetate to suppress IFN-γ+/−TNF-α induced intestinal epithelial activation in association with their HDAC inhibitory capacity, while studying the canonical and non-canonical STAT1 pathway. HT-29 were activated with IFN-γ+/−TNF-α and treated with short chain fatty acids (SCFAs) or histone deacetylase (HDAC) inhibitors. CXCL10 release and protein and mRNA expression of proteins involved in the STAT1 pathway were determined. All SCFAs dose-dependently inhibited CXCL10 release of the cells after activation with IFN-γ or IFN-γ+TNF-α. Butyrate was the most effective, completely preventing CXCL10 induction. Butyrate did not affect phosphorylated STAT1, nor phosphorylated NFκB p65, but inhibited IRF9 and phosphorylated JAK2 protein expression in activated cells. Additionally, butyrate inhibited <i>CXCL10</i>, <i>SOCS1</i>, <i>JAK2</i> and <i>IRF9</i> mRNA in activated cells. The effect of butyrate was mimicked by class I HDAC inhibitors and a general HDAC inhibitor Trichostatin A. Butyrate is the most potent inhibitor of CXCL10 release compared to other SCFAs and acts via HDAC inhibition. This causes downregulation of <i>CXCL10</i>, <i>JAK2</i> and <i>IRF9</i> genes, resulting in a decreased IRF9 protein expression which inhibits the non-canonical pathway and CXCL10 transcription. |
| first_indexed | 2024-03-09T11:44:59Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T11:44:59Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-f0b94b8086af4f34a245bbae9d7651862023-11-30T23:24:52ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-04-01237398010.3390/ijms23073980Butyrate Prevents Induction of CXCL10 and Non-Canonical IRF9 Expression by Activated Human Intestinal Epithelial Cells via HDAC InhibitionSandra G. P. J. Korsten0Laura Peracic1Luka M. B. van Groeningen2Mara A. P. Diks3Herman Vromans4Johan Garssen5Linette E. M. Willemsen6Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The NetherlandsDivision of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The NetherlandsDivision of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The NetherlandsDivision of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The NetherlandsTiofarma B.V., 3261 ME Oud-Beijerland, The NetherlandsDivision of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The NetherlandsDivision of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The NetherlandsNon-communicable diseases are increasing and have an underlying low-grade inflammation in common, which may affect gut health. To maintain intestinal homeostasis, unwanted epithelial activation needs to be avoided. This study compared the efficacy of butyrate, propionate and acetate to suppress IFN-γ+/−TNF-α induced intestinal epithelial activation in association with their HDAC inhibitory capacity, while studying the canonical and non-canonical STAT1 pathway. HT-29 were activated with IFN-γ+/−TNF-α and treated with short chain fatty acids (SCFAs) or histone deacetylase (HDAC) inhibitors. CXCL10 release and protein and mRNA expression of proteins involved in the STAT1 pathway were determined. All SCFAs dose-dependently inhibited CXCL10 release of the cells after activation with IFN-γ or IFN-γ+TNF-α. Butyrate was the most effective, completely preventing CXCL10 induction. Butyrate did not affect phosphorylated STAT1, nor phosphorylated NFκB p65, but inhibited IRF9 and phosphorylated JAK2 protein expression in activated cells. Additionally, butyrate inhibited <i>CXCL10</i>, <i>SOCS1</i>, <i>JAK2</i> and <i>IRF9</i> mRNA in activated cells. The effect of butyrate was mimicked by class I HDAC inhibitors and a general HDAC inhibitor Trichostatin A. Butyrate is the most potent inhibitor of CXCL10 release compared to other SCFAs and acts via HDAC inhibition. This causes downregulation of <i>CXCL10</i>, <i>JAK2</i> and <i>IRF9</i> genes, resulting in a decreased IRF9 protein expression which inhibits the non-canonical pathway and CXCL10 transcription.https://www.mdpi.com/1422-0067/23/7/3980intestinal epithelial cellsshort chain fatty acidsCXCL10STAT1 pathway |
| spellingShingle | Sandra G. P. J. Korsten Laura Peracic Luka M. B. van Groeningen Mara A. P. Diks Herman Vromans Johan Garssen Linette E. M. Willemsen Butyrate Prevents Induction of CXCL10 and Non-Canonical IRF9 Expression by Activated Human Intestinal Epithelial Cells via HDAC Inhibition International Journal of Molecular Sciences intestinal epithelial cells short chain fatty acids CXCL10 STAT1 pathway |
| title | Butyrate Prevents Induction of CXCL10 and Non-Canonical IRF9 Expression by Activated Human Intestinal Epithelial Cells via HDAC Inhibition |
| title_full | Butyrate Prevents Induction of CXCL10 and Non-Canonical IRF9 Expression by Activated Human Intestinal Epithelial Cells via HDAC Inhibition |
| title_fullStr | Butyrate Prevents Induction of CXCL10 and Non-Canonical IRF9 Expression by Activated Human Intestinal Epithelial Cells via HDAC Inhibition |
| title_full_unstemmed | Butyrate Prevents Induction of CXCL10 and Non-Canonical IRF9 Expression by Activated Human Intestinal Epithelial Cells via HDAC Inhibition |
| title_short | Butyrate Prevents Induction of CXCL10 and Non-Canonical IRF9 Expression by Activated Human Intestinal Epithelial Cells via HDAC Inhibition |
| title_sort | butyrate prevents induction of cxcl10 and non canonical irf9 expression by activated human intestinal epithelial cells via hdac inhibition |
| topic | intestinal epithelial cells short chain fatty acids CXCL10 STAT1 pathway |
| url | https://www.mdpi.com/1422-0067/23/7/3980 |
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