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-M TP-PE) is a new biologic agent presently in clinical trials for metast atic osteosarcoma and melanoma. The mechanism of L-MTP-PE antitumor ac tivity is linked to its activation of monocyte tumoricidal function. T he purpose of this study was to determine whether L-MTP-PE affected th e 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 pers isted 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. Lipopolys accharide stimulation caused a rapid increase in cytokine expression f ollowed 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 expre ssion in lymphocytes. The early up-regulation of all five cytokines wa s 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 expos ure to L-MTP-PE. The subsequent production and secretion of these cyto kine proteins may play a role in L-MTP-PE antitumor activity.