Induction of tumor necrosis factor-alpha (TNF-alpha) by interleukin-12 p40 monomer and homodimer in microglia and macrophages

J Neurochem. 2003 Jul;86(2):519-28. doi: 10.1046/j.1471-4159.2003.01864.x.


The present study was undertaken to explore the role of interleukin-12 (IL-12) p40 in the expression of TNF-alpha 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-alpha and the expression of TNF-alpha mRNA in BV-2 microglial cells. In addition to BV-2 microglial cells, p70, p402 and p40 also induced the production of TNF-alpha in mouse primary microglia and peritoneal macrophages. As the activation of both NF-kappaB and CCAAT/enhancer binding protein beta (C/EBPbeta) is important for the expression of TNF-alpha in microglial cells, we investigated the effect of p40 on the activation of NF-kappaB as well as C/EBPbeta. Activation of NF-kappaB as well as C/EBPbeta by p40 and inhibition of p40-induced expression of TNF-alpha by Deltap65, a dominant-negative mutant of p65, and DeltaC/EBPbeta, a dominant-negative mutant of C/EBPbeta, suggests that p40 induces the expression of TNF-alpha through the activation of NF-kappaB and C/EBPbeta. 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-alpha through the inhibition of C/EBPbeta, but not that of NF-kappaB, whereas SB203580, an inhibitor of p38 MAPK, inhibited p40-induced expression of TNF-alpha through the inhibition of both NF-kappaB and C/EBPbeta. This study delineates a novel biological function of p40 in inducing TNF-alpha in microglia and macrophages.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Protein-beta / metabolism
  • Cells, Cultured
  • Dimerization
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation / drug effects*
  • Interleukin-12 / pharmacology*
  • Interleukin-12 Subunit p40
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / metabolism*
  • Mice
  • Microglia / cytology
  • Microglia / drug effects
  • Microglia / metabolism*
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / metabolism
  • Protein Subunits / pharmacology*
  • RNA, Messenger / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*
  • p38 Mitogen-Activated Protein Kinases


  • CCAAT-Enhancer-Binding Protein-beta
  • Interleukin-12 Subunit p40
  • NF-kappa B
  • Protein Subunits
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Interleukin-12
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases