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Keywords:

  • CCAAT/enhancer binding protein β;
  • IL-12p40;
  • MAP kinases;
  • microglia;
  • NF-κB;
  • TNF-α

Abstract

The present study was undertaken to explore the role of interleukin-12 (IL-12) p40 in the expression of TNF-α in microglia. Interestingly, we have found that IL-12 p70, p402 (the p40 homodimer) and p40 (the p40 monomer) dose-dependently induced the production of TNF-α and the expression of TNF-α mRNA in BV-2 microglial cells. In addition to BV-2 microglial cells, p70, p402 and p40 also induced the production of TNF-α in mouse primary microglia and peritoneal macrophages. As the activation of both NF-κB and CCAAT/enhancer binding protein β (C/EBPβ) is important for the expression of TNF-α in microglial cells, we investigated the effect of p40 on the activation of NF-κB as well as C/EBPβ. Activation of NF-κB as well as C/EBPβ by p40 and inhibition of p40-induced expression of TNF-α by Δp65, a dominant-negative mutant of p65, and ΔC/EBPβ, a dominant-negative mutant of C/EBPβ, suggests that p40 induces the expression of TNF-α through the activation of NF-κB and C/EBPβ. In addition, we show that p40 induced the activation of both extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK). Interestingly, PD98059, an inhibitor of ERK, inhibited p40-induced expression of TNF-α through the inhibition of C/EBPβ, but not that of NF-κB, whereas SB203580, an inhibitor of p38 MAPK, inhibited p40-induced expression of TNF-α through the inhibition of both NF-κB and C/EBPβ. This study delineates a novel biological function of p40 in inducing TNF-α in microglia and macrophages.