G(AnH)MTetra, a naturally occurring 1,6-anhydro muramyl dipeptide, induces granulocyte colony-stimulating factor expression in human monocytes: a molecular analysis

Abstract

N-Acetylglucosaminyl-1,6-anhydro-N-acetylmuramyl-L-alanyl-D-isoglutam yl-m- diaminopimelyl-D-alanine [G (Anh)MTetra], a naturally occurring breakdown product of peptidoglycan from bacterial cell walls, was studied for its ability to induce granulocyte colony-stimulating factor (G-CSF) mRNA and protein expression in human adherent monocytes. Resting monocytes did not express G-CSF mRNA or secrete G-CSF protein. In contrast, monocytes exposed to G(Anh)MTetra showed a dose-dependent increase in G-CSF mRNA accumulation, which correlates with the secretion of G-CSF protein. Maximal levels of G-CSF mRNA were reached within 2 h of activation. Expression of G-CSF was mediated by an increase in the stability of G-CSF transcripts rather than by an increase in the transcription rate of the G-CSF gene. Experiments with the protein synthesis inhibitor cycloheximide revealed that G(Anh)MTetra-induced G-CSF mRNA expression was independent of new protein synthesis. Furthermore, it was shown that the effect of G(Anh)MTetra was regulated by a protein kinase C-dependent pathway, whereas protein kinase A and tyrosine kinases were not involved. Finally, it was shown that G(Anh)MTetra also induced G-CSF mRNA expression in human endothelial cells. The data indicate that, besides lipopolysaccharide, other naturally occurring bacterial cell wall components are able to induce G-CSF expression in different hematopoietic cells.

Bacterial modulins: a novel class of virulence factors which cause host tissue pathology by inducing cytokine synthesis.

“…Peptidoglycans released in vivo will be degraded by host enzymes, and such breakdown products may, in turn, have cytokine-inducing activity. Two recent papers report that N-acetylglucosaminyl-1,6-anhydro-N-acetylmuramyl-L-alanyl-D-isoglutamyl-m-diaminopimelyl-D-alanine [G(Anh)MTetra], a naturally occurring breakdown product of peptidoglycan, at concentrations as low as 50 ng/ml, induces the synthesis of IL-1␤, IL-6, and G-CSF by human monocytes (39,40). This finding confirms the initial study of Dinarello and Krueger (38).…”

High resolution crystal structures of the Escherichia coli lytic transglycosylase slt70 and its complex with a peptidoglycan fragment

“…Since their activity is directed towards the glycosidic bonds in the glycan strands, they offer a target for structure-based design of novel antibiotics distinctly different from the penicillins and related b-lactam antibacterials, whose main target form the enzymes involved in the synthesis and cleavage of the peptide linkage between the glycan strands (Waxman & Strominger, 1983). A second interest is related to their 1,6-anhydromuropeptide products, which show a number of unusual biological activities in mammals, ranging from the ability to induce sleep (Martin et al, 1984;Johannsen, 1993), to stimulate the immune response (Dokter et al, 1994) and to properties that are related to the pathogenesis of Gram-negative bacteria like Neisseria gonorrhoeae and Bordetella pertussis (Melly et al, 1984;Cookson et al, 1989). The molecular basis for the activities shown by the 1,6-anhydromuropeptides is still not understood.…”

Serum levels of stem cell factor and thrombopoietin are markedly decreased in fulminant hepatic failure patients with a poor prognosis

“…Granulocyte colony stimulating factor is produced by monocytes, macrophages, fibroblasts and endothelial cells, and is a hematopoietic factor that acts on neutrophils or multipotent bone marrow stem cells 36 . G‐CSF supports cell growth and differentiation of preneutrophils and hematopoietic stem cells, and promotes mobilization of mature neutrophils and stem cells into the circulation 37 .…”