Inhibition of miR-146a Expression and Regulation of Endotoxin Tolerance by Rhesus Theta-Defensin-1
Theta- (θ-) defensins are pleiotropic host defense peptides with antimicrobial- and immune-modulating activities. Immune stimulation of cells with lipopolysaccharide (LPS, endotoxin) activates proinflammatory gene expression and cytokine secretion, both of which are attenuated by rhesus theta-defens...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Hindawi Limited
2023-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2023/8387330 |
| _version_ | 1826998442025549824 |
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| author | Prasad Tongaonkar Katie K. Trinh André J. Ouellette Michael E. Selsted |
| author_facet | Prasad Tongaonkar Katie K. Trinh André J. Ouellette Michael E. Selsted |
| author_sort | Prasad Tongaonkar |
| collection | DOAJ |
| description | Theta- (θ-) defensins are pleiotropic host defense peptides with antimicrobial- and immune-modulating activities. Immune stimulation of cells with lipopolysaccharide (LPS, endotoxin) activates proinflammatory gene expression and cytokine secretion, both of which are attenuated by rhesus theta-defensin-1 (RTD-1) inhibition of NF-κB and MAP kinase pathways. Endotoxin tolerance is a condition that ensues when cells have an extended primary exposure to low levels of LPS, resulting in resistance to a subsequent LPS challenge. Recognition of LPS by Toll-like receptor-4 (TLR4) activates NF-κB, elevating levels of microRNA-146a (miR-146a), which targets IRAK1 and TRAF6 transcripts to reduce their protein levels and inhibits TLR signaling on secondary LPS stimulation. Here, we report that RTD-1 suppressed the expression of miR-146a and stabilized the IRAK1 protein in immune-stimulated, monocytic THP-1 cells. Cells that had primary exposure to LPS became endotoxin-tolerant, as evident from their failure to secrete TNF-α upon secondary endotoxin challenge. However, cells incubated with RTD-1 during the primary LPS stimulation secreted TNF-α after secondary LPS stimulation in an RTD-1 dose-dependent manner. Consistent with this, compared to the control treatment, cells treated with RTD-1 during primary LPS stimulation had increased NF-κB activity after secondary LPS stimulation. These results show that RTD-1 suppresses endotoxin tolerance by inhibiting the NF-κB pathway and demonstrates a novel inflammatory role for RTD-1 that is mediated by the downregulation of miR-146a during the innate immune response. |
| first_indexed | 2024-04-09T16:08:41Z |
| format | Article |
| id | doaj.art-72610aae30b3400fa69f61fcc6a9439e |
| institution | Directory Open Access Journal |
| issn | 1466-1861 |
| language | English |
| last_indexed | 2025-02-18T10:15:19Z |
| publishDate | 2023-01-01 |
| publisher | Hindawi Limited |
| record_format | Article |
| series | Mediators of Inflammation |
| spelling | doaj.art-72610aae30b3400fa69f61fcc6a9439e2024-11-02T05:32:18ZengHindawi LimitedMediators of Inflammation1466-18612023-01-01202310.1155/2023/8387330Inhibition of miR-146a Expression and Regulation of Endotoxin Tolerance by Rhesus Theta-Defensin-1Prasad Tongaonkar0Katie K. Trinh1André J. Ouellette2Michael E. Selsted3Department of Pathology and Laboratory MedicineDepartment of Pathology and Laboratory MedicineDepartment of Pathology and Laboratory MedicineDepartment of Pathology and Laboratory MedicineTheta- (θ-) defensins are pleiotropic host defense peptides with antimicrobial- and immune-modulating activities. Immune stimulation of cells with lipopolysaccharide (LPS, endotoxin) activates proinflammatory gene expression and cytokine secretion, both of which are attenuated by rhesus theta-defensin-1 (RTD-1) inhibition of NF-κB and MAP kinase pathways. Endotoxin tolerance is a condition that ensues when cells have an extended primary exposure to low levels of LPS, resulting in resistance to a subsequent LPS challenge. Recognition of LPS by Toll-like receptor-4 (TLR4) activates NF-κB, elevating levels of microRNA-146a (miR-146a), which targets IRAK1 and TRAF6 transcripts to reduce their protein levels and inhibits TLR signaling on secondary LPS stimulation. Here, we report that RTD-1 suppressed the expression of miR-146a and stabilized the IRAK1 protein in immune-stimulated, monocytic THP-1 cells. Cells that had primary exposure to LPS became endotoxin-tolerant, as evident from their failure to secrete TNF-α upon secondary endotoxin challenge. However, cells incubated with RTD-1 during the primary LPS stimulation secreted TNF-α after secondary LPS stimulation in an RTD-1 dose-dependent manner. Consistent with this, compared to the control treatment, cells treated with RTD-1 during primary LPS stimulation had increased NF-κB activity after secondary LPS stimulation. These results show that RTD-1 suppresses endotoxin tolerance by inhibiting the NF-κB pathway and demonstrates a novel inflammatory role for RTD-1 that is mediated by the downregulation of miR-146a during the innate immune response.http://dx.doi.org/10.1155/2023/8387330 |
| spellingShingle | Prasad Tongaonkar Katie K. Trinh André J. Ouellette Michael E. Selsted Inhibition of miR-146a Expression and Regulation of Endotoxin Tolerance by Rhesus Theta-Defensin-1 Mediators of Inflammation |
| title | Inhibition of miR-146a Expression and Regulation of Endotoxin Tolerance by Rhesus Theta-Defensin-1 |
| title_full | Inhibition of miR-146a Expression and Regulation of Endotoxin Tolerance by Rhesus Theta-Defensin-1 |
| title_fullStr | Inhibition of miR-146a Expression and Regulation of Endotoxin Tolerance by Rhesus Theta-Defensin-1 |
| title_full_unstemmed | Inhibition of miR-146a Expression and Regulation of Endotoxin Tolerance by Rhesus Theta-Defensin-1 |
| title_short | Inhibition of miR-146a Expression and Regulation of Endotoxin Tolerance by Rhesus Theta-Defensin-1 |
| title_sort | inhibition of mir 146a expression and regulation of endotoxin tolerance by rhesus theta defensin 1 |
| url | http://dx.doi.org/10.1155/2023/8387330 |
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