G(ANH)MTETRA, A NATURALLY-OCCURRING 1,6-ANHYDRO MURAMYL DIPEPTIDE, INDUCES GRANULOCYTE-COLONY-STIMULATING FACTOR EXPRESSION IN HUMAN MONOCYTES - A MOLECULAR ANALYSIS

-L-alanyl-D-isoglutamyl-m-diaminopimelyl-D-alanine [G(Anh)MTetra], a n aturally occurring breakdown product of peptidoglycan from bacterial c ell walls, was studied for its ability to induce granulocyte colony-st imulating 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 d ose-dependent increase in G-CSF mRNA accumulation, which correlates wi th the secretion of G-CSF protein. Maximal levels of G-CSF mRNA were r eached within 2 h of activation. Expression of G-CSF was mediated by a n increase in the stability of G-CSF transcripts rather than by an inc rease in the transcription rate of the G-CSF gene. Experiments with th e protein synthesis inhibitor cycloheximide revealed that G(Anh)MTetra -induced G-CSF mRNA expression was independent of new protein synthesi s, Furthermore, it was shown that the effect of G(Anh)MTetra was regul ated 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 cel ls. The data indicate that, besides lipopolysaccharide, other naturall y occurring bacterial cell wall components are able to induce G-CSF ex pression in different hematopoietic cells.