G(ANH)MTETRA, A NATURAL BACTERIAL-CELL WALL BREAKDOWN PRODUCT, INDUCES INTERLEUKIN-1-BETA AND INTERLEUKIN-6 EXPRESSION IN HUMAN MONOCYTES -A STUDY OF THE MOLECULAR MECHANISMS INVOLVED IN INFLAMMATORY CYTOKINEEXPRESSION

It is believed that induction of cytokine expression by bacterial cell wall components plays a role in the development and course of sepsis. However, most attention has been focused on lipopolysaccharide (LPS). We studied the ability of -L-alanyl-D-isoglutamyl-m-diaminopimelyl-D- alanine (G(Anh)MTetra), a naturally occurring breakdown product of pep tidoglycan that is produced by soluble lytic transglycosylase of Esche richia coli, to induce cytokine expression in human monocytes. G(Anh)M Tetra was found to strongly induce interleukin (IL)-1 beta and IL-6 mR NA expression after 2 h and IL-1 beta and IL-6 protein secretion after 48 h of activation. The increase in mRNA accumulation was at least pa rtly due to an increase in the transcription rates of the respective g enes and was accompanied by a strong induction of nuclear factor-kappa B and activator protein-1 transcription factor expression. Experiment s using inhibitors of protein kinase C, protein kinase A, and tyrosine kinase-dependent pathways revealed that G(Anh)MTetra-induced IL-1 bet a and IL-6 mRNA expression involves activation of an H7-inhibitable pa thway. By using the protein synthesis inhibitor cycloheximide, it was shown that G(Anh)MTetra-induced IL-6 mRNA expression depends on the sy nthesis of new protein, whereas G(Anh)MTetra-induced IL-1 beta mRNA ac cumulation does not. When responses to G(Anh)MTetra were compared with those to LPS and muramyldipeptide (MDP), it was found that the optima l response to G(Anh)MTetra induction was similar to that of LPS but si gnificantly higher than the response to MDP. Furthermore, maximal G(An h)MTetra-induced IL-1 beta and IL-6 mRNA expression could be enhanced by co stimulation with LPS or MDP, suggesting that different receptors and/or transduction pathways were involved. These results indicate th at G(Anh)MTetra induces IL-1 beta and IL-6 expression in human monocyt es suggesting a possible role for G(Anh)MTetra in the release of cytok ines during sepsis.