IL‐12 p40 homodimer, the so‐called biologically inactive molecule, induces nitric oxide synthase in microglia via IL‐12Rβ1

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/EBPβ, but not NF‐κB, whereas the p38 pathway relayed the signal from p40 2 to iNOS expression via both NF‐κB and C/EBPβ. Furthermore, by using microglia from IL‐12Rβ1 (−/−) and IL‐12Rβ2 (−/−) mice or siRNA against IL‐12Rβ1 and IL‐12Rβ2, we demonstrate that p40 2 induced the expression of iNOS in microglia via IL‐12Rβ1–(ERK+p38)–(NF‐κB +C/EBPβ) pathway. In contrast, both IL‐12Rβ1 and IL‐12Rβ2 were involved for IL‐12 p70‐induced microglial expression of iNOS. Although IL‐12Rβ1 coupled p70 to NF‐κB and C/EBPβ, IL‐12Rβ2 was responsible for p70‐mediated activation of GAS. This study delineates a new role of IL‐12Rβ1 and IL‐12Rβ2 for the expression of iNOS and production of NO in microglia that may participate in the pathogenesis of neuroinflammatory diseases. © 2009 Wiley‐Liss, Inc.