Rac mediates TNF-induced cytokine production via modulation of NF-kappaB.
TNF is a key factor in a variety of inflammatory diseases. Here we report that TNF induced pro-inflammatory cytokine synthesis of IL-6 and IL-8 is mediated by the Rho GTPase Rac. TNF induces p42/p44, p54 and p38 MAPK kinase; these kinases have been implicated in control of cytokine synthesis. Howeve...
| Main Authors: | , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2008
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| _version_ | 1797064186776256512 |
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| author | Williams, L Lali, F Willetts, K Balague, C Godessart, N Brennan, F Feldmann, M Foxwell, B |
| author_facet | Williams, L Lali, F Willetts, K Balague, C Godessart, N Brennan, F Feldmann, M Foxwell, B |
| author_sort | Williams, L |
| collection | OXFORD |
| description | TNF is a key factor in a variety of inflammatory diseases. Here we report that TNF induced pro-inflammatory cytokine synthesis of IL-6 and IL-8 is mediated by the Rho GTPase Rac. TNF induces p42/p44, p54 and p38 MAPK kinase; these kinases have been implicated in control of cytokine synthesis. However, over-expression of a dominant negative form of Rac strongly inhibited TNF-induced p42/44 MAPK kinase activation, but had little effect upon JNK and no effect upon p38 MAPK activity. Another key signalling pathway controlling cytokine expression is NF-kappaB. When analyzing TNF-induced NF-kappaB activity via luciferase-reporter assays or via EMSA, we were able to show that the dominant negative version of Rac could completely abrogate TNF-induced NF-kappaB activity. In addition, we also observed that inhibition of the ERK pathway led to a reduction in TNF-induced NF-kappaB transcriptional activity; this was accompanied by an ablation of TNF-induced p65 phosphorylation at serine 276. This would suggest that TNF-induced activation of Rac, lies upstream of NF-kappaB activation, and that the inhibition of this pathway results in inhibition of cytokine production. |
| first_indexed | 2024-03-06T21:10:39Z |
| format | Journal article |
| id | oxford-uuid:3e087408-4323-44bf-bc45-a05d63123b65 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:10:39Z |
| publishDate | 2008 |
| record_format | dspace |
| spelling | oxford-uuid:3e087408-4323-44bf-bc45-a05d63123b652022-03-26T14:23:01ZRac mediates TNF-induced cytokine production via modulation of NF-kappaB.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:3e087408-4323-44bf-bc45-a05d63123b65EnglishSymplectic Elements at Oxford2008Williams, LLali, FWilletts, KBalague, CGodessart, NBrennan, FFeldmann, MFoxwell, BTNF is a key factor in a variety of inflammatory diseases. Here we report that TNF induced pro-inflammatory cytokine synthesis of IL-6 and IL-8 is mediated by the Rho GTPase Rac. TNF induces p42/p44, p54 and p38 MAPK kinase; these kinases have been implicated in control of cytokine synthesis. However, over-expression of a dominant negative form of Rac strongly inhibited TNF-induced p42/44 MAPK kinase activation, but had little effect upon JNK and no effect upon p38 MAPK activity. Another key signalling pathway controlling cytokine expression is NF-kappaB. When analyzing TNF-induced NF-kappaB activity via luciferase-reporter assays or via EMSA, we were able to show that the dominant negative version of Rac could completely abrogate TNF-induced NF-kappaB activity. In addition, we also observed that inhibition of the ERK pathway led to a reduction in TNF-induced NF-kappaB transcriptional activity; this was accompanied by an ablation of TNF-induced p65 phosphorylation at serine 276. This would suggest that TNF-induced activation of Rac, lies upstream of NF-kappaB activation, and that the inhibition of this pathway results in inhibition of cytokine production. |
| spellingShingle | Williams, L Lali, F Willetts, K Balague, C Godessart, N Brennan, F Feldmann, M Foxwell, B Rac mediates TNF-induced cytokine production via modulation of NF-kappaB. |
| title | Rac mediates TNF-induced cytokine production via modulation of NF-kappaB. |
| title_full | Rac mediates TNF-induced cytokine production via modulation of NF-kappaB. |
| title_fullStr | Rac mediates TNF-induced cytokine production via modulation of NF-kappaB. |
| title_full_unstemmed | Rac mediates TNF-induced cytokine production via modulation of NF-kappaB. |
| title_short | Rac mediates TNF-induced cytokine production via modulation of NF-kappaB. |
| title_sort | rac mediates tnf induced cytokine production via modulation of nf kappab |
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