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Individual LPS Responsiveness Depends on the Variation of Toll-Like Receptor(TLR) Expression Level
( Jaekal Jun ),( Edward Abraham ),( Tania Azam ),( Mihai G. Netea ),( Charles A. Dinarello ),( Jong Seok Lim ),( Young Yang ),( Do Young Yoon ),( Soo Hyun Kim ) 한국미생물생명공학회 2007 Journal of microbiology and biotechnology Vol.17 No.11
Joosten, Leo A B,Crisan, Tania O,Azam, Tania,Cleophas, Maartje C P,Koenders, Marije I,van de Veerdonk, Frank L,Netea, Mihai G,Kim, Soohyun,Dinarello, Charles A BMJ Publishing Group Ltd 2016 Annals of the Rheumatic Diseases Vol.75 No.6
<P>Objectives In the present study, we generated a new protein, recombinant human alpha-1-anti-trypsin (AAT)-IgG1 Fc fusion protein (AAT-Fc), and evaluated its properties to suppress inflammation and interleukin (IL)-1 beta in a mouse model of gouty arthritis. Methods A combination of monosodium urate (MSU) crystals and the fatty acid C16.0 (MSU/C16.0) was injected intra-articularly into the knee to induce gouty arthritis. Joint swelling, synovial cytokine production and histopathology were determined after 4 h. AAT-Fc was evaluated for inhibition of MSU/C16.0-induced IL-1 beta release from human blood monocytes and for inhibition of extracellular IL-1 beta precursor processing. Results AAT-Fc markedly suppressed MSU/C16.0-induced joint inflammation by 85-91% (p<0.001). Ex vivo production of IL-1 beta and IL-6 from cultured synovia were similarly reduced (63% and 65%, respectively). The efficacy of 2.0 mg/kg AAT-Fc in reducing inflammation was comparable to 80 mg/kg of plasma-derived AAT. Injection of AAT-Fc into mice increased circulating levels of endogenous IL-1 receptor antagonist by fourfold. We also observed that joint swelling was reduced by 80%, cellular infiltration by 95% and synovial production of IL-1 beta by 60% in transgenic mice expressing low levels of human AAT. In vitro, AAT-Fc reduced MSU/C16.0-induced release of IL-1 beta from human blood monocytes and inhibited proteinase-3-mediated extracellular processing of the IL-1 beta precursor into active IL-1 beta. Conclusions A single low dose of AAT-Fc is highly effective in reducing joint inflammation in this model of acute gouty arthritis. Considering the long-term safety of plasma-derived AAT use in humans, subcutaneous AAT-Fc emerges as a promising therapy for gout attacks.</P>