| Crynodeb: | 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.
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