Defining therapeutic targets by using adenovirus: blocking NF-kappaB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators.
The role of the transcription factor NF-kappaB in the pathogenesis of rheumatoid arthritis has long been a subject of controversy. We used an adenoviral technique of blocking NF-kappaB through overexpression of the inhibitory subunit IkappaBalpha, which has the advantage that it can be used in the d...
| Main Authors: | , , , |
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| Format: | Journal article |
| Language: | English |
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1999
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| _version_ | 1797061299050381312 |
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| author | Bondeson, J Foxwell, B Brennan, F Feldmann, M |
| author_facet | Bondeson, J Foxwell, B Brennan, F Feldmann, M |
| author_sort | Bondeson, J |
| collection | OXFORD |
| description | The role of the transcription factor NF-kappaB in the pathogenesis of rheumatoid arthritis has long been a subject of controversy. We used an adenoviral technique of blocking NF-kappaB through overexpression of the inhibitory subunit IkappaBalpha, which has the advantage that it can be used in the diseased tissue itself, with >90% of the synovial macrophages, fibroblasts, and T cells infected. We found that the spontaneous production of tumor necrosis factor alpha and other pro-inflammatory cytokines is NF-kappaB-dependent in rheumatoid synovial tissue, in contrast to the main anti-inflammatory mediators, like IL-10 and -11, and the IL-1 receptor antagonist. Of even more interest, IkappaBalpha overexpression inhibited the production of matrix metalloproteinases 1 and 3 while not affecting their tissue inhibitor. Blocking NF-kappaB in the rheumatoid joint thus has a very beneficial profile, reducing both the inflammatory response and the tissue destruction. The adenoviral technique described here has widespread applicability, allowing rapid testing of the effects of blocking a potential therapeutic target in either cultures of normal cells or in the diseased tissue itself. |
| first_indexed | 2024-03-06T20:29:06Z |
| format | Journal article |
| id | oxford-uuid:306fbae2-2bfc-420c-a5d1-a77ba62229f6 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:29:06Z |
| publishDate | 1999 |
| record_format | dspace |
| spelling | oxford-uuid:306fbae2-2bfc-420c-a5d1-a77ba62229f62022-03-26T13:01:26ZDefining therapeutic targets by using adenovirus: blocking NF-kappaB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:306fbae2-2bfc-420c-a5d1-a77ba62229f6EnglishSymplectic Elements at Oxford1999Bondeson, JFoxwell, BBrennan, FFeldmann, MThe role of the transcription factor NF-kappaB in the pathogenesis of rheumatoid arthritis has long been a subject of controversy. We used an adenoviral technique of blocking NF-kappaB through overexpression of the inhibitory subunit IkappaBalpha, which has the advantage that it can be used in the diseased tissue itself, with >90% of the synovial macrophages, fibroblasts, and T cells infected. We found that the spontaneous production of tumor necrosis factor alpha and other pro-inflammatory cytokines is NF-kappaB-dependent in rheumatoid synovial tissue, in contrast to the main anti-inflammatory mediators, like IL-10 and -11, and the IL-1 receptor antagonist. Of even more interest, IkappaBalpha overexpression inhibited the production of matrix metalloproteinases 1 and 3 while not affecting their tissue inhibitor. Blocking NF-kappaB in the rheumatoid joint thus has a very beneficial profile, reducing both the inflammatory response and the tissue destruction. The adenoviral technique described here has widespread applicability, allowing rapid testing of the effects of blocking a potential therapeutic target in either cultures of normal cells or in the diseased tissue itself. |
| spellingShingle | Bondeson, J Foxwell, B Brennan, F Feldmann, M Defining therapeutic targets by using adenovirus: blocking NF-kappaB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators. |
| title | Defining therapeutic targets by using adenovirus: blocking NF-kappaB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators. |
| title_full | Defining therapeutic targets by using adenovirus: blocking NF-kappaB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators. |
| title_fullStr | Defining therapeutic targets by using adenovirus: blocking NF-kappaB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators. |
| title_full_unstemmed | Defining therapeutic targets by using adenovirus: blocking NF-kappaB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators. |
| title_short | Defining therapeutic targets by using adenovirus: blocking NF-kappaB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators. |
| title_sort | defining therapeutic targets by using adenovirus blocking nf kappab inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti inflammatory mediators |
| work_keys_str_mv | AT bondesonj definingtherapeutictargetsbyusingadenovirusblockingnfkappabinhibitsbothinflammatoryanddestructivemechanismsinrheumatoidsynoviumbutsparesantiinflammatorymediators AT foxwellb definingtherapeutictargetsbyusingadenovirusblockingnfkappabinhibitsbothinflammatoryanddestructivemechanismsinrheumatoidsynoviumbutsparesantiinflammatorymediators AT brennanf definingtherapeutictargetsbyusingadenovirusblockingnfkappabinhibitsbothinflammatoryanddestructivemechanismsinrheumatoidsynoviumbutsparesantiinflammatorymediators AT feldmannm definingtherapeutictargetsbyusingadenovirusblockingnfkappabinhibitsbothinflammatoryanddestructivemechanismsinrheumatoidsynoviumbutsparesantiinflammatorymediators |