The immunomodulator AS-101 inhibits IL-10 release and augments TNF alpha and IL-1 alpha release by mouse and human mononuclear phagocytes.
AS-101 is a tellurium-based compound with known immunomodulating properties. The ability of AS-101 to potentiate the effects of chemotherapeutic drugs and augment cytokine production in vivo has led to clinical trials on AS-101 which are currently being carried out in cancer patients. In the present study we show that AS-101 selectively augments the release of TNF alpha and IL-1 alpha and inhibits the release of IL-10 by lipopolysaccharide (LPS)-stimulated mouse peritoneal macrophages and human monocytes. It does not significantly affect the release of IL-6 or leukemia inhibitory factor (LIF). By itself AS-101 does not induce the release of any of these cytokines. Analysis of IL-10 and TNF alpha RNA levels using semiquantitative PCR reveals that AS-101 blocks the transcription of IL-10 mRNA, but does not significantly affect TNF alpha mRNA. Although both AS-101 and interferon (IFN)-gamma inhibit IL-10, AS-101, unlike IFN-gamma, does not prime macrophages for LPS-induced nitric oxide release and does not appear to significantly affect monocyte HLA-DR expression. Our data suggest that AS-101 is a partial IFN-gamma agonist and may explain the shift toward the release of Th-1 type cytokines observed in AS-101-treated patients.
Strassmann
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G
Department of Immunology, Otsuka-America Pharmaceutical Inc., Rockville, Maryland 20850, USA.
Kambayashi
T
T
Jacob
C O
CO
Sredni
D
D
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D005030:Ethylenes / Q000494:pharmacology*; D006684:HLA-DR Antigens / Q000096:biosynthesis; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism*; D016753:Interleukin-10 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D005030:Ethylenes; D006684:HLA-DR Antigens; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C054105:ammonium trichloro(dioxoethylene-O,O'-)tellurate; D007371:Interferon-gamma