Liposomal muramyl tripeptide up-regulates interleukin-1 alpha, interleukin-1 beta, tumor necrosis factor-alpha, interleukin-6 and interleukin-8 gene expression in human monocytes.
Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) is a new biologic agent presently in clinical trials for metastatic osteosarcoma and melanoma. The mechanism of L-MTP-PE antitumor activity is linked to its activation of monocyte tumoricidal function. The purpose of this study was to determine whether L-MTP-PE affected the expression of cytokine genes in monocytes. Monocyte interleukin (IL)-1 alpha, IL-1 beta, IL-6, IL-8 and tumor necrosis factor (TNF)-alpha expression were all up-regulated after a 2-h incubation with L-MTP-PE. The increased expression of IL-1 alpha, IL-1 beta, IL-6 and IL-8 persisted up to 72 h. Increased TNF-alpha expression declined by 24 h. The kinetics of cytokine expression stimulated by L-MTP-PE were different from those seen after lipopolysaccharide (LPS) stimulation. Lipopolysaccharide stimulation caused a rapid increase in cytokine expression followed by a rapid decline. L-MTP-PE did not affect the expression of these cytokines in lymphocytes, nor did L-MTP-PE upregulate IL-2 expression in lymphocytes. The early up-regulation of all five cytokines was due to an increase in the transcriptional activity. Modification of mRNA stability was not detected at 2 h but was seen after a 24-h exposure to L-MTP-PE. The subsequent production and secretion of these cytokine proteins may play a role in L-MTP-PE antitumor activity.
Asano
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Department of Cell Biology, University of Texas M. D. Anderson Cancer Center, Houston.
McWatters
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Matsushima
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Kleinerman
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D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D008081:Liposomes; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015854:Up-Regulation
D000276:Adjuvants, Immunologic; D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D008081:Liposomes; D010714:Phosphatidylethanolamines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C037144:mifamurtide; D000119:Acetylmuramyl-Alanyl-Isoglutamine