Inflammatory disease status and response to TNF blockade are associated with mechanisms of endotoxin tolerance
The mechanisms of endotoxin tolerance (ET), which down-regulate inflammation, are well described in response to exogenous toll-like receptor ligands, but few studies have focused on ET-associated mechanisms in inflammatory disease. As blocking TNF can attenuate the development of ET, the effect of a...
| Auteurs principaux: | , , , , , , , , |
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| Format: | Journal article |
| Langue: | English |
| Publié: |
Elsevier
2024
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| _version_ | 1826317805376503808 |
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| author | Taylor, PC Clanchy, FIL Borghese, F Bystrom, J Balog, A Penn, H Hull, DN Williams, RO Mageed, RA |
| author_facet | Taylor, PC Clanchy, FIL Borghese, F Bystrom, J Balog, A Penn, H Hull, DN Williams, RO Mageed, RA |
| author_sort | Taylor, PC |
| collection | OXFORD |
| description | The mechanisms of endotoxin tolerance (ET), which down-regulate inflammation, are well described in response to exogenous toll-like receptor ligands, but few studies have focused on ET-associated mechanisms in inflammatory disease. As blocking TNF can attenuate the development of ET, the effect of anti-TNF on the expression of key ET-associated molecules in inflammatory auto-immune disease was measured; changes in inflammatory gene expression were confirmed using an ET bioassay. The expression of immunomodulatory molecules was measured in a murine model of arthritis treated with anti-TNF and the expression of ET-associated molecules was measured in whole blood in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) patients, before and after therapy. The expression of ET-associated genes was also measured in RA patient monocytes before and after therapy, in anti-TNF responders and non-responders. <em>Tnfaip3</em>, <em>Ptpn6</em> and <em>Irak3</em> were differentially expressed in affected paws, spleens, lymph nodes and circulating leucocytes in experimental murine arthritis treated with anti-TNF. Prior to therapy, the expression of <em>TNFAIP3</em>, <em>INPP5D</em>, <em>PTPN6</em>, <em>CD38</em> and <em>SIGIRR</em> in whole blood differed between human healthy controls and RA or AS patients. In blood monocytes from RA patients, the expression of <em>TNFAIP3</em> was significantly reduced by anti-TNF therapy in non-responders. Prior to therapy, anti-TNF non-responders had higher expression of <em>TNFAIP3</em> and <em>SLPI</em>, compared to responders. Although the expression of <em>TNFAIP3</em> was significantly higher in RA non-responders prior to treatment, the post-treatment reduction to a level similar to responders did not coincide with a clinical response to therapy. |
| first_indexed | 2025-03-11T16:59:44Z |
| format | Journal article |
| id | oxford-uuid:98f139ab-8e9b-4fc6-baf6-7d8bc91efae9 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2025-03-11T16:59:44Z |
| publishDate | 2024 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:98f139ab-8e9b-4fc6-baf6-7d8bc91efae92025-03-07T16:16:23ZInflammatory disease status and response to TNF blockade are associated with mechanisms of endotoxin toleranceJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:98f139ab-8e9b-4fc6-baf6-7d8bc91efae9EnglishSymplectic ElementsElsevier2024Taylor, PCClanchy, FILBorghese, FBystrom, JBalog, APenn, HHull, DNWilliams, ROMageed, RAThe mechanisms of endotoxin tolerance (ET), which down-regulate inflammation, are well described in response to exogenous toll-like receptor ligands, but few studies have focused on ET-associated mechanisms in inflammatory disease. As blocking TNF can attenuate the development of ET, the effect of anti-TNF on the expression of key ET-associated molecules in inflammatory auto-immune disease was measured; changes in inflammatory gene expression were confirmed using an ET bioassay. The expression of immunomodulatory molecules was measured in a murine model of arthritis treated with anti-TNF and the expression of ET-associated molecules was measured in whole blood in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) patients, before and after therapy. The expression of ET-associated genes was also measured in RA patient monocytes before and after therapy, in anti-TNF responders and non-responders. <em>Tnfaip3</em>, <em>Ptpn6</em> and <em>Irak3</em> were differentially expressed in affected paws, spleens, lymph nodes and circulating leucocytes in experimental murine arthritis treated with anti-TNF. Prior to therapy, the expression of <em>TNFAIP3</em>, <em>INPP5D</em>, <em>PTPN6</em>, <em>CD38</em> and <em>SIGIRR</em> in whole blood differed between human healthy controls and RA or AS patients. In blood monocytes from RA patients, the expression of <em>TNFAIP3</em> was significantly reduced by anti-TNF therapy in non-responders. Prior to therapy, anti-TNF non-responders had higher expression of <em>TNFAIP3</em> and <em>SLPI</em>, compared to responders. Although the expression of <em>TNFAIP3</em> was significantly higher in RA non-responders prior to treatment, the post-treatment reduction to a level similar to responders did not coincide with a clinical response to therapy. |
| spellingShingle | Taylor, PC Clanchy, FIL Borghese, F Bystrom, J Balog, A Penn, H Hull, DN Williams, RO Mageed, RA Inflammatory disease status and response to TNF blockade are associated with mechanisms of endotoxin tolerance |
| title | Inflammatory disease status and response to TNF blockade are associated with mechanisms of endotoxin tolerance |
| title_full | Inflammatory disease status and response to TNF blockade are associated with mechanisms of endotoxin tolerance |
| title_fullStr | Inflammatory disease status and response to TNF blockade are associated with mechanisms of endotoxin tolerance |
| title_full_unstemmed | Inflammatory disease status and response to TNF blockade are associated with mechanisms of endotoxin tolerance |
| title_short | Inflammatory disease status and response to TNF blockade are associated with mechanisms of endotoxin tolerance |
| title_sort | inflammatory disease status and response to tnf blockade are associated with mechanisms of endotoxin tolerance |
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