Macrophage stimulation with murabutide, an HIV-suppressive muramyl peptidederivative, selectively activates extracellular signal-regulated kinases 1and 2, C/EBP beta and STAT1: role of CD14 and Toll-like receptors 2 and 4

The smallest unit of bacterial peptidoglycans known to be endowed with biol ogical activities is muramyl dipeptide (MDP). A clinically acceptable synth etic derivative of MDP, namely murabutide (MB), has been found to present i nteresting pharmacological properties and to suppress HIV-1, replication in monocyte-derived macrophages (MDM). We have addressed the signaling events activated in MDM following stimulation with either MB or the potent immuno stimulant LPS. We also examined whether signaling by muramyl peptides invol ves the use of cell surface receptors, including CD14 and Toll-like recepto r 2 (TLR2) or TLR4 that are known to be signal-transducing receptors for ot her bacterial cell wall components. We demonstrate that, unlike LPS, the sa fe immunomodulator MB selectively activates extracellular signal-regulated kinases (Erk) 1/2, in the absence of detectable dun N-terminal kinase (JNK) or p38 mitogen-activated kinase activation. Furthermore, STAT1 activation but weak or no activation of STAT3 or STAT5 respectively, could be detected in MB-stimulated MDM. Using MonoMac6 cells, we observed high C/EBP beta an d AP-1 but weaker and transient NF kappaB activation by MB. Moreover, the t runcated form of C/EBP beta, known to repress HIV-1 transcription, was dete cted in extracts from MB-treated THP-I cells. Surprisingly, neither MB nor MDP were able to transduce signals via CD14 and TLR2 or 4. These findings p resent major differences in the early cell activation process between LPS a nd muramyl peptides, and strongly argue for the implication of co-receptors other than TLR2 and TLR4 in mediating the signaling events induced by defi ned subunits of bacterial peptidoglycans.