The synthetic tellurium compound, AS101, is a novel inhibitor of IL-1beta converting enzyme.
The organotellurium compound, trichloro(dioxoethylene-O,O') tellurate (AS101) has been shown previously to exert diverse biologic activities both in vitro and in vivo. This compound was recently found to react with thiols and to catalyze their oxidation. This property of AS101 raises the possibility that it may serve as a cysteine protease inhibitor. In the present study, using a substrate-specific enzymatic assay, we show that treatment of caspase-1 (interleukin-1beta [IL-1beta] converting enzyme [ICE]) with AS101 inhibits its enzymatic activity in a dose-dependent manner. Moreover, the results show that AS101 treatment causes a significant reduction in the active form of IL-18 and IL-1beta in peripheral blood mononuclear cells (PBMC) and in human HaCat keratinocytes. We further demonstrate that the inhibitory effect of AS101 does not involve nitric oxide (NO) or interferon-gamma (IFN-gamma), two possible regulators of IL-18 production, and does not occur at the mRNA level, suggesting a posttranscriptional mechanism of action. More importantly, AS101 downregulates IL-18 and IL-1beta serum levels in a mouse model of lipopolysaccharide (LPS)-induced sepsis, resulting in increased survival. Recent studies emphasize the pathophysiologic role of IL-18 and IL-1beta in a variety of inflammatory diseases. Thus, their blockage by the nontoxic compound, AS101, currently used in clinical studies, may provide clinical advantage in the treatment of these diseases.
Brodsky
Miri
M
C.A.I.R. Institute, The Safdié AIDS and Immunology Research Center, The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
Yosef
Sigal
S
Galit
Rushkin
R
Albeck
Michael
M
Longo
Dan L
DL
Albeck
Amnon
A
Sredni
Benjamin
B
D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D005030:Ethylenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics; D018805:Sepsis / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D015843:Serpins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D015996:Survival Rate; D013691:Tellurium / Q000737:chemistry*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014764:Viral Proteins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use
D061945:Caspase Inhibitors; D005030:Ethylenes; D020382:Interleukin-18; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D015843:Serpins; D014764:Viral Proteins; D009569:Nitric Oxide; C054105:ammonium trichloro(dioxoethylene-O,O'-)tellurate; D007371:Interferon-gamma; C074641:interleukin-1beta-converting enzyme inhibitor; D020170:Caspase 1; D013755:Tetradecanoylphorbol Acetate; D013691:Tellurium