Liposomal muramyl tripeptide up-regulates interleukin-1α, interleukin- 1β, tumor necrosis factor-α, 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)-1α, IL-1β, IL-6, IL- 8 and tumor necrosis factor (TNF)-α expression were all up-regulated after a 2-h incubation with L-MTP-PE. The increased expression of IL-1α, IL-1β, IL- 6 and IL-8 persisted up to 72 h. Increased TNF-α 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, not 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.