Molecular mechanisms involved in the regulation of cytokine production by muramyl dipeptide
Résumé
Muramyl dipeptide (MDP), a component of peptidoglycan, interacts with NOD2 stimulating the NOD2/RIP2 complex to activate signaling pathways important for anti-bacterial defence. Here we demonstrate that the protein kinase activity of RIP2 has two functions, namely to limit the strength of downstream signaling and to stabilise the active enzyme. Thus pharmacological inhibition of RIP2 kinase with either SB 203580 or PP2 induces a rapid and drastic decrease in the level of the RIP2 protein, which may explain why these RIP2 inhibitors block MDP-stimulated downstream signaling and the production of IL-1β and TNFα. We also show that RIP2 induces the activation of the protein kinase TAK1, that a dominant negative mutant of TAK1 inhibits RIP2-induced activation of JNK and p38α MAPK, and that signaling downstream of NOD2 or RIP2 is reduced by the TAK1 inhibitor 5Z-7-oxo-zeaenol or in TAK1-deficient cells. We also show that MDP activates ERK1/ERK2 and p38α MAPK in human PBMC and that both MAP kinases and TAK1 activity are required for MDP-induced production of IL-1β and TNFα in these cells. Taken together, our results indicate that the MDP-NOD2/RIP2 and LPS-TLR4 signaling pathways converge at the level of TAK1 and that many subsequent events that lead to the production of pro-inflammatory cytokines are common to both pathways.
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