Mercury inhibits nitric oxide production but activates proinflammatory cytokine expression in murine macrophage: Differential modulation of NF-κB and p38 MAPK signaling pathways

Mercury is well known to adversely affect the immune system; however, little is known regarding its molecular mechanisms. Macrophages are major producers of nitric oxide (NO) and this signaling molecule is important in the regulation of immune responses. The present study was designed to determine the impact of mercury on NO and cytokine production and to investigate the signaling pathways involved. The murine macrophage cell line J774A.1 was used to study the effects of low-dose inorganic mercury on the production of NO and proinflammatory cytokines. Cells were treated with mercury in the presence or absence of lipopolysaccharide (LPS). Mercury (5-20μM) dose-dependently decreased the production of NO in LPS-stimulated cells. Concomitant decreases in the expression of inducible nitric oxide synthase (iNOS) mRNA and protein were detected. Treatment of J774A.1 cells with mercury alone did not affect the production of NO nor the expression of iNOS mRNA or protein. Interestingly, mercury alone stimulated the expression of tumor necrosis factor α (TNFα), and increased LPS-induced TNFα and interleukin-6 mRNA expression. Mercury inhibited LPS-induced nuclear translocation of nuclear factor κB (NF-κB) but had no effect alone. In contrast, mercury activated p38 mitogen-activated protien kinase (p38 MAPK) and additively increased LPS-induced p38 MAPK phosphorylation. These results indicate that mercury suppresses NO synthesis by inhibition of the NF-κB pathway and modulates cytokine expression by p38 MAPK activation in J774A.1 macrophage cells.