| Abstract |
MPMBP is a novel non-nitrogen-containing bisphosphonate (non-NBP) which possesses anti-bone resorptive activity and an antioxidant side chain. This study aimed to assess the effects of MPMBP on the production of proinflammatory cytokines and chemokines by the macrophage-like cell line, J774.1, in the presence of Toll-like receptor (TLR) agonists. J774.1 cells were pretreated with or without MPMBP for 5 min, and then incubated with or without Pam3Cys-Ser-(Lys)4 (Pam3CSK4, a TLR2 agonist) or lipid A (a TLR4 agonist) for 24 h. MPMBP down-regulated TLR2 ligand-induced production of IL-6, MCP-1, MIP-1α, and TNF-α, but not TLR4 ligand-induced proinflammatory cytokine production, and was not cytotoxic in J774.1 cells. Cu-CPT22, a TLR2 antagonist, down-regulated Pam3CSK4-induced production of IL-6, MCP-1, and MIP-1α, but not TNF-α. MPMBP inhibited the translocation of NF-κB p65, but not p50, RelB, or p52, and inhibited the activation of JNK, but not p38 MAPK or ERK, in J774.1 cells stimulated with Pam3CSK4. Moreover, MPMBP did not down-regulate AP-1 activation in J774.1 cells stimulated with Pam3CSK4 or lipid A. Our findings suggest that MPMBP inhibits proinflammatory cytokine production in J774.1 cells by suppressing NF-κB p65 activation in the TLR2, but not TLR4, pathway.
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