Synergistic effect of muramyl dipeptide with heat shock protein 70 from Mycobacterium tuberculosis on immune activation

Abstract

Heat shock protein 70 from Mycobacterium tuberculosis (Mtb Hsp70) has been known to modulate immune response including dendritic cell activation. Muramyl dipeptide (MDP) is an immunoreactive derivative of peptidoglycan from all Gram-negative and Gram-positive bacteria and recognized to be responsible for function of Freund's complete adjuvant. In this study, we evaluated effect of MDP on in vitro activation of bone marrow derived dendritic cells (BMDCs) and in vivo production of cytokines and chemokines induced by Mtb Hsp70. MDP treatment with Mtb Hsp70 dramatically increased production of IL-6, IL-12p40 and TNF-alpha in BMDCs compared with Mtb Hsp70 alone whereas these effects were abolished in Nod2-deficient BMDCs. Phosphorylation of I kappa B-alpha and ERK and impairment of phagocytosis, which is an indicator of DC maturation were enhanced by MDP co-treatment with Mtb hsp70 in BMDCs. In addition, ability of Mtb Hsp70-stimulated BMDCs to induce IFN-gamma productions of T cells was increased by MDP co-treatment. Finally, intraperitoneal injection of MDP with Mtb Hsp70 dramatically increased production of IL-6, CXCL-1 and CCL2 in serum compared with Mtb hsp70 injection. Our study showed the synergistic effects of MDP with Mtb Hsp70 on DCs and in vivo immune activation. The use of MDP with Mtb Hsp70 to induce immune activation may provide an effective strategy for vaccination to treat cancer and protect against pathogens.