Lipopolysaccharide and tumor necrosis factor-α synergy potentiate serum-dependent responses of rat macrophages

Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) are major mediators of sepsis and multiple organ failure. Serum-mediated macrophage activation requires lipopolysaccharide (LPS) and its serum binding protein, lipopolysaccharide binding protein as a ligand for the receptor CD14. This study was designed to determine whether cytokines participate in regulation of serum-mediated LPS activation. Rat macrophages were stimulated with LPS with and without TNF-α or IL-1β and activation was determined by detection of TNF-α by specific enzyme-linked immunosorbent assay or TNF-α mRNA by Northern blot analysis. The addition of TNF-α but not IL-1β, in the presence of serum, leads to potentiation of macrophage activation after LPS stimulation. This effect could be specifically inhibited by neutralization of LPS with polymyxin B or an antibody against TNF-α. This study shows that LPS and TNF-α synergize to potentiate serum-mediated macrophage activation. These results demonstrate another element of the control mechanism of cytokine secretion following macrophage activation in sepsis.