The transcriptional response of human macrophages to murabutide reflects a spectrum of biological effects for the synthetic immunomodulator

Abstract

SUMMARY The synthetic immunomodulator murabutide (MB) presents multiple biological activities with minimal toxicity in animals and in man. Although MB is known to target cells of the reticuloendothelial system and to regulate cytokine synthesis, the molecular mechanisms underlying several of its biological effects are still largely unknown. In an effort to define cellular factors implicated in the immunomodulatory and HIV‐suppressive activities of MB, we have undertaken profiling the regulated expression of genes in human monocyte‐derived macrophages (MDM) following a 6‐h stimulation with this synthetic glycopeptide. Oligonucleotide microarray analysis was performed on RNA samples of differentiated MDM from four separate donors, using probe sets corresponding to 1081 genes. We have identified, in a reproducible fashion, the enhanced expression of 40 genes and the inhibition of 16 others in MB‐treated MDM. These regulated genes belonged to different families of immune mediators or their receptors, transcription factors and kinases, matrix proteins and their inhibitors, ion channels and transporters, and proteins involved in cell metabolic pathways. Additional verification of the regulated expression of selected genes was carried out using Northern blots or the quantification of released proteins in MDM cultures. The profile of MB‐regulated genes in MDM provides a molecular basis for some of its previously reported biological activities, and reveals new set of genes targeted by the immunomodulator suggesting potential application in novel therapeutic indications.

Muramyl Dipeptide and its Derivatives: Peptide Adjuvant in Immunological Disorders and Cancer Therapy

“…Murabutide (MB), for example, is a synthetic immunomodulator derived from MDP that enhances non-specific resistance to bacterial and viral infections without fever and decreases the lethality of LPS in mice 29–32 . It has also been observed to synergize with antiviral and anti-inflammatory cytokines such as IFN-α as well as increase the anti-tumor effects of IFN-α and IL-2 in mouse models 33, 34 .…”

Expression of costimulatory molecules (CD80, CD86, CD28, CD152), accessory molecules (TCR αβ, TCR γδ) and T cell lineage molecules (CD4+, CD8+) in PBMC of leprosy patients using Mycobacterium leprae antigen (MLCWA) with murabutide and T cell peptide of Trat protein

“…Murabutide is known to regulate monocyte -macrophage function with the release of monokines that are involved in autoregulation of some of the immune cells. Recently, the molecular mechanism by which murabutide promotes various immunopharmacological effects on monocyte derived macrophages has been described using RNA microarray [11]. This study was extended to demonstrate the role of such observation in the expression of the costimulatory molecules and other accessory molecules like TCR ah and gy and CD4+ and CD8+ phenotype during constitutive and activated state.…”

Translation of peptidoglycan metabolites into immunotherapeutics

“…As an additional acute response, PG sensing can elicit the secretion of multiple cytokines. For example, stimulation of human monocyte‐derived macrophages with murabutide 10 led to an increase in expression and secretion of numerous cytokines including IL‐1β, IL‐6, TNFɑ, RANTES, IL‐8 and MIP‐1β . Additionally, stimulation of macrophages with romurtide 9 led to increased secretion of colony‐stimulating factors to promote hematopoiesis …”