Abstract：
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. Tnfaip3, Ptpn6 and Irak3 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 TNFAIP3, INPP5D, PTPN6, CD38 and SIGIRR in whole blood differed between human healthy controls and RA or AS patients. In blood monocytes from RA patients, the expression of TNFAIP3 was significantly reduced by anti-TNF therapy in non-responders. Prior to therapy, anti-TNF non-responders had higher expression of TNFAIP3 and SLPI, compared to responders. Although the expression of TNFAIP3 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.
摘要：
内毒素耐受（ET）的机制，下调炎症，很好地描述了对外源性Toll样受体配体的反应，但很少有研究关注炎症性疾病中ET相关机制。由于阻断TNF可以减弱ET的发展，检测了抗TNF对炎症性自身免疫性疾病中关键ET相关分子表达的影响;使用ET生物测定法证实了炎症基因表达的变化.在用抗TNF治疗的关节炎小鼠模型中测量免疫调节分子的表达，并在类风湿关节炎（RA）和强直性脊柱炎（AS）患者的全血中测量ET相关分子的表达，治疗前后。还测量了治疗前后RA患者单核细胞中ET相关基因的表达，在抗TNF应答者和非应答者中。Tnfaip3，Ptpn6和Irak3在受影响的爪子中差异表达，脾脏,用抗TNF治疗的实验性小鼠关节炎的淋巴结和循环白细胞。治疗前,TNFAIP3、INPP5D、全血中的PTPN6、CD38和SIGIRR在人健康对照和RA或AS患者之间存在差异。在RA患者的血液单核细胞中，在无应答者中,抗TNF治疗显著降低了TNFAIP3的表达.治疗前,抗TNF无反应者有较高的TNFAIP3和SLPI表达，与响应者相比。尽管TNFAIP3的表达在治疗前RA无应答者中显著较高,治疗后降低至与应答者相似的水平与临床治疗应答不一致.
