کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
9245588 | 1209949 | 2005 | 17 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Infliximab induces potent anti-inflammatory responses by outside-to-inside signals through transmembrane TNF-α
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کلمات کلیدی
c-Jun NH2-terminal kinaseTNFTNF-RmTNFTransmembrane TNF-αETAIFXTACECHXJnkMAPK - MAPKROS - ROSamino acid - آمینو اسیدTNF-α converting enzyme - آنزیم تبدیل TNF-αetanercept - اتانرسپت Infliximab - اینفیلیکسیمابSER - برای بودنSerine - سرینcycloheximide - سیکلوهایسیمیدtumor necrosis factor - فاکتور نکروز تومورwild-type - نوع وحشیmitogen-activated protein kinase - پروتئین کیناز فعال با mitogenReactive oxygen species - گونههای فعال اکسیژنTNF receptor - گیرنده TNF
موضوعات مرتبط
علوم پزشکی و سلامت
پزشکی و دندانپزشکی
بیماریهای گوارشی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Background & Aims: Both infliximab (chimeric anti-tumor necrosis factor [TNF]-α antibody) and etanercept (p75 TNF-α receptor/immunoglobulin G fusion protein) are effective against rheumatoid arthritis, but only infliximab induces clinical remission in Crohn's disease. To clarify this difference in clinical efficacy, we investigated reverse signaling through transmembrane TNF-α (mTNF) by these 2 anti-TNF agents. Methods: We stably transfected wild-type and cytoplasmic serine-replaced mutant forms of mTNF in human Jurkat T cells. Cells were stimulated with infliximab and etanercept and then analyzed for E-selectin expression, reactive oxygen species accumulation, apoptosis, and cell cycle distribution by flow cytometry. Interleukin-10 and interferon-γ were measured by enzyme-linked immunosorbent assay. Phospho-c-Jun NH2-terminal kinase, Bax, Bak, p21WAF1/CIP1, caspase-8, and caspase-3 were examined by immunoblotting. Results: Both anti-TNF agents induced E-selectin expression, but only infliximab induced interleukin-10 production, apoptosis, and G0/G1 cell cycle arrest. Apoptosis and cell cycle arrest were abolished by substitution of all 3 cytoplasmic serine residues of mTNF by alanine residues. Infliximab induced accumulation of reactive oxygen species and up-regulation of Bax, Bak, and p21WAF1/CIP1 proteins, suggesting the involvement of p53 activation. Moreover, phosphorylation of c-Jun NH2-terminal kinase was necessary for infliximab-induced apoptosis and cell cycle arrest. Conclusions: We revealed the mTNF motifs and the downstream intracellular molecular events essential for reverse signaling through mTNF. The biologic effects of mTNF elicited by infliximab should be important action mechanisms of this potent anti-inflammatory agent in addition to the neutralization of soluble TNF-α. These observations will provide insight into the novel role of mTNF in inflammation.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Gastroenterology - Volume 128, Issue 2, February 2005, Pages 376-392
Journal: Gastroenterology - Volume 128, Issue 2, February 2005, Pages 376-392
نویسندگان
Hiroki Mitoma, Takahiko Horiuchi, Nobuaki Hatta, Hiroshi Tsukamoto, Shin-Ichi Harashima, Yuji Kikuchi, Junji Otsuka, Seiichi Okamura, Shigeru Fujita, Mine Harada,