IL-12 p40 homodimer, the so-called biologically inactive molecule, induces nitric oxide synthase in microglia via IL-12R beta 1

Glia. 2009 Nov 1;57(14):1553-65. doi: 10.1002/glia.20869.


Earlier we have demonstrated that IL-12 p40 homodimer (p40(2)) induces the expression of inducible nitric oxide synthase (iNOS) in microglia. This study was undertaken to investigate underlying mechanisms required for IL-12 p40(2)- and IL-12 p70-induced expression of iNOS in microglia. IL-12 p40(2) alone induced the activation of both extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK). Interestingly, the ERK pathway coupled p40(2) to iNOS expression via C/EBP beta, but not NF-kappaB, whereas the p38 pathway relayed the signal from p40(2) to iNOS expression via both NF-kappaB and C/EBP beta. Furthermore, by using microglia from IL-12R beta 1 (-/-) and IL-12R beta 2 (-/-) mice or siRNA against IL-12R beta 1 and IL-12R beta 2, we demonstrate that p40(2) induced the expression of iNOS in microglia via IL-12R beta 1-(ERK+p38)-(NF-kappaB +C/EBP beta) pathway. In contrast, both IL-12R beta 1 and IL-12R beta 2 were involved for IL-12 p70-induced microglial expression of iNOS. Although IL-12R beta 1 coupled p70 to NF-kappaB and C/EBP beta, IL-12R beta 2 was responsible for p70-mediated activation of GAS. This study delineates a new role of IL-12R beta 1 and IL-12R beta 2 for the expression of iNOS and production of NO in microglia that may participate in the pathogenesis of neuroinflammatory diseases.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • Cells, Cultured
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Interleukin-12 / metabolism
  • Interleukin-12 Subunit p40 / metabolism*
  • MAP Kinase Signaling System
  • Mice
  • Mice, Knockout
  • Microglia / enzymology
  • Microglia / metabolism*
  • NF-kappa B / metabolism
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type II / metabolism*
  • RNA, Small Interfering / metabolism
  • Receptors, Interleukin-12 / genetics
  • Receptors, Interleukin-12 / metabolism*
  • Serum Albumin / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Il12rb1 protein, mouse
  • Il12rb2 protein, mouse
  • Interleukin-12 Subunit p40
  • NF-kappa B
  • RNA, Small Interfering
  • Receptors, Interleukin-12
  • Serum Albumin
  • Interleukin-12
  • Nitric Oxide
  • Nitric Oxide Synthase Type II
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases