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IL‐12 p40 homodimer, the so‐called biologically inactive molecule, induces nitric oxide synthase in microglia via IL‐12Rβ1
Author(s) -
Jana Malabendu,
Dasgupta Subhajit,
Pal Utpal,
Pahan Kalipada
Publication year - 2009
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.20869
Subject(s) - microglia , nitric oxide synthase , mapk/erk pathway , p38 mitogen activated protein kinases , microbiology and biotechnology , signal transduction , nitric oxide , kinase , biology , chemistry , inflammation , immunology , endocrinology
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.