Paradoxical Anti-Inflammatory Actions of TNF-α: Inhibition of IL-12 and IL-23 via TNF Receptor 1 in Macrophages and Dendritic Cells

IL-12 and TNF-α are central proinflammatory cytokines produced by macrophages and dendritic cells. Disregulation of TNF-α is associated with sepsis and autoimmune diseases such as rheumatoid arthritis. However, new evidence suggests an anti-inflammatory role for TNF-α. TNF-α-treated murine macrophages produced less IL-12p70 and IL-23, after stimulation with IFN-γ and LPS. Frequency of IL-12p40-producing macrophages correspondingly decreased as measured by intracellular cytokine staining. IL-12p40 production was also inhibited in dendritic cells. TNFR1 was established as the main receptor involved in IL-12p40 regulation, because IL-12p40 levels were not affected by TNF-α in TNFR1 −/− -derived macrophages. Macrophages activated during Listeria monocytogenes infection were more susceptible to inhibition by TNF-α than cells from naive animals, which suggests a regulatory role for TNF-α in later stages of infection. This nonapoptotic anti-inflammatory regulation of IL-12 and IL-23 is an important addition to the multitude of TNF-α-induced responses determined by cell-specific receptor signaling.