Mechanism of three inhibitors of TACE in blocking the converting of pro-TNF alpha into sTNF alpha.
The effects of inhibitors of TNF alpha converting enzyme (TACE) on TNF alpha secretion were studied to develop an approach to interfere inflammation processes. The HL-60 cell lines were stimulated in vitro with LPS intravenously for different time to establish the cellular model of inflammation and simultaneously induce in vivo inflammation animal model by LPS The cytotoxic effects of soluble TNF alpha were checked using MTT colorimetric method to determine the rate of cell proliferation. The level of expression of TACE was detected by using RT-PCR, FCM and immuno-histochemical technique respectively. It was found Chinese medicine Reduqing (RDQ) could inhibit the transcription of TNF alpha mRNA induced by LPS stimulation (P < 0.01, compared with the control). The antioligodeoxyribonucleotide (anti-ODN) of TNF alpha mRNA could inhibit 78.9% of TNF alpha secretion. The mimic peptides of TACE substrates with hydroxamine group showed potency in vivo and in vitro against converting of pro-TNF alpha. It was concluded that all the three types of TACE inhibitors can regulate the expression of TACE at different levels and inhibit sTNF alpha secretion, indicating TACE is a novel target for inflammation therapy.
Wang
Zhen
Z
Department of Pharmacology, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030.
Wang
Yin
Y
Zhu
Kongli
K
Guo
Lianjun
L
Yang
Yuzhen
Y
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008070:Lipopolysaccharides; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D009838:Oligodeoxyribonucleotides / Q000037:antagonists & inhibitors; D011498:Protein Precursors / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
D004365:Drugs, Chinese Herbal; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; D011498:Protein Precursors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C061153:tumor necrosis factor precursor; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human