Inhibition of IL-1 Signaling by Antisense Oligonucleotide-mediated Exon Skipping of IL-1 Receptor Accessory Protein (IL-1RAcP)
The cytokine interleukin 1(IL-1) initiates a wide range of proinflammatory cascades and its inhibition has been shown to decrease inflammation in a variety of diseases. IL-1 receptor accessory protein (IL-1RAcP) is an indispensible part of the IL-1R complex that stabilizes IL-1/IL-1R interaction and...
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Elsevier
2013-01-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253116301263 |
| _version_ | 1818419222599958528 |
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| author | A Seda Yılmaz-Eliş Annemieke Aartsma-Rus Peter AC 't Hoen Huma Safdar Cor Breukel Bart JM van Vlijmen Judith van Deutekom Sjef de Kimpe Gert-Jan van Ommen J Sjef Verbeek |
| author_facet | A Seda Yılmaz-Eliş Annemieke Aartsma-Rus Peter AC 't Hoen Huma Safdar Cor Breukel Bart JM van Vlijmen Judith van Deutekom Sjef de Kimpe Gert-Jan van Ommen J Sjef Verbeek |
| author_sort | A Seda Yılmaz-Eliş |
| collection | DOAJ |
| description | The cytokine interleukin 1(IL-1) initiates a wide range of proinflammatory cascades and its inhibition has been shown to decrease inflammation in a variety of diseases. IL-1 receptor accessory protein (IL-1RAcP) is an indispensible part of the IL-1R complex that stabilizes IL-1/IL-1R interaction and plays an important role in the signal transduction of the receptor complex. The soluble form of IL-1RAcP (sIL-1RAcP) contains only the extracellular domain and serves as a natural inhibitor of IL-1 signaling. Therefore, increasing sIL-1RAcP levels might be an attractive therapeutic strategy to inhibit IL-1–driven inflammation. To achieve this we designed specific antisense oligonucleotides (AON), to redirect pre-mRNA IL-1RAcP splicing by skipping of the transmembrane domain encoding exon 9. This would give rise to a novel Δ9IL-1RAcP mRNA encoding a soluble, secreted form of IL-1RAcP, which might have similar activity as natural sIL-1RAcP. AON treatment resulted in exon 9 skipping both in vitro and in vivo. A single dose injection of 10 mg AON/kg body weight induced 90% skipping in mouse liver during at least 5 days. The truncated mRNA encoded for a secreted, soluble Δ9IL-1RAcP protein. IL-1RAcP skipping resulted in a substantial inhibition of IL-1 signaling in vitro. These results indicate that skipping of the transmembrane encoding exon 9 of IL-1RAcP using specific AONs might be a promising therapeutic strategy in a variety of chronic inflammatory diseases. |
| first_indexed | 2024-12-14T12:35:09Z |
| format | Article |
| id | doaj.art-e2a9f8d60d6d4ae68cee84a3933fcb10 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-14T12:35:09Z |
| publishDate | 2013-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-e2a9f8d60d6d4ae68cee84a3933fcb102022-12-21T23:01:04ZengElsevierMolecular Therapy: Nucleic Acids2162-25312013-01-012C10.1038/mtna.2012.58Inhibition of IL-1 Signaling by Antisense Oligonucleotide-mediated Exon Skipping of IL-1 Receptor Accessory Protein (IL-1RAcP)A Seda Yılmaz-Eliş0Annemieke Aartsma-Rus1Peter AC 't Hoen2Huma Safdar3Cor Breukel4Bart JM van Vlijmen5Judith van Deutekom6Sjef de Kimpe7Gert-Jan van Ommen8J Sjef Verbeek9Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The NetherlandsCenter for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The NetherlandsCenter for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Hematology, Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The NetherlandsCenter for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Hematology, Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The NetherlandsProsensa Therapeutics BV, Leiden, The NetherlandsProsensa Therapeutics BV, Leiden, The NetherlandsCenter for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The NetherlandsCenter for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The NetherlandsThe cytokine interleukin 1(IL-1) initiates a wide range of proinflammatory cascades and its inhibition has been shown to decrease inflammation in a variety of diseases. IL-1 receptor accessory protein (IL-1RAcP) is an indispensible part of the IL-1R complex that stabilizes IL-1/IL-1R interaction and plays an important role in the signal transduction of the receptor complex. The soluble form of IL-1RAcP (sIL-1RAcP) contains only the extracellular domain and serves as a natural inhibitor of IL-1 signaling. Therefore, increasing sIL-1RAcP levels might be an attractive therapeutic strategy to inhibit IL-1–driven inflammation. To achieve this we designed specific antisense oligonucleotides (AON), to redirect pre-mRNA IL-1RAcP splicing by skipping of the transmembrane domain encoding exon 9. This would give rise to a novel Δ9IL-1RAcP mRNA encoding a soluble, secreted form of IL-1RAcP, which might have similar activity as natural sIL-1RAcP. AON treatment resulted in exon 9 skipping both in vitro and in vivo. A single dose injection of 10 mg AON/kg body weight induced 90% skipping in mouse liver during at least 5 days. The truncated mRNA encoded for a secreted, soluble Δ9IL-1RAcP protein. IL-1RAcP skipping resulted in a substantial inhibition of IL-1 signaling in vitro. These results indicate that skipping of the transmembrane encoding exon 9 of IL-1RAcP using specific AONs might be a promising therapeutic strategy in a variety of chronic inflammatory diseases.http://www.sciencedirect.com/science/article/pii/S2162253116301263antisense oligonucleotideexon skippinginflammationinterleukin 1soluble IL-1R accessory protein |
| spellingShingle | A Seda Yılmaz-Eliş Annemieke Aartsma-Rus Peter AC 't Hoen Huma Safdar Cor Breukel Bart JM van Vlijmen Judith van Deutekom Sjef de Kimpe Gert-Jan van Ommen J Sjef Verbeek Inhibition of IL-1 Signaling by Antisense Oligonucleotide-mediated Exon Skipping of IL-1 Receptor Accessory Protein (IL-1RAcP) Molecular Therapy: Nucleic Acids antisense oligonucleotide exon skipping inflammation interleukin 1 soluble IL-1R accessory protein |
| title | Inhibition of IL-1 Signaling by Antisense Oligonucleotide-mediated Exon Skipping of IL-1 Receptor Accessory Protein (IL-1RAcP) |
| title_full | Inhibition of IL-1 Signaling by Antisense Oligonucleotide-mediated Exon Skipping of IL-1 Receptor Accessory Protein (IL-1RAcP) |
| title_fullStr | Inhibition of IL-1 Signaling by Antisense Oligonucleotide-mediated Exon Skipping of IL-1 Receptor Accessory Protein (IL-1RAcP) |
| title_full_unstemmed | Inhibition of IL-1 Signaling by Antisense Oligonucleotide-mediated Exon Skipping of IL-1 Receptor Accessory Protein (IL-1RAcP) |
| title_short | Inhibition of IL-1 Signaling by Antisense Oligonucleotide-mediated Exon Skipping of IL-1 Receptor Accessory Protein (IL-1RAcP) |
| title_sort | inhibition of il 1 signaling by antisense oligonucleotide mediated exon skipping of il 1 receptor accessory protein il 1racp |
| topic | antisense oligonucleotide exon skipping inflammation interleukin 1 soluble IL-1R accessory protein |
| url | http://www.sciencedirect.com/science/article/pii/S2162253116301263 |
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