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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
09:12

Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates

Published on: January 30, 2014

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

Malabendu Jana1, Subhajit Dasgupta, Utpal Pal

  • 1Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612, USA.

Glia
|March 24, 2009
PubMed

Insights

Interleukin-12 (IL-12) p40 homodimer activates microglia to express inducible nitric oxide synthase (iNOS) via specific signaling pathways involving IL-12R beta 1. IL-12 p70 utilizes both IL-12R beta 1 and IL-12R beta 2.

Area of Science:

  • Neuroimmunology
  • Molecular Biology
  • Cell Signaling

Background:

  • Microglia play a crucial role in neuroinflammation.
  • Interleukin-12 (IL-12) is a key cytokine in immune responses.
  • Inducible nitric oxide synthase (iNOS) is an enzyme implicated in inflammatory processes.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying IL-12 p40 homodimer (p40(2)) and IL-12 p70-induced iNOS expression in microglia.
  • To identify the specific roles of IL-12 receptor beta 1 (IL-12Rβ1) and IL-12 receptor beta 2 (IL-12Rβ2) in these signaling pathways.

Main Methods:

  • Investigated signaling pathways including extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK).
  • Utilized microglia from IL-12Rβ1 (-/-) and IL-12Rβ2 (-/-) knockout mice.
  • Employed small interfering RNA (siRNA) to silence IL-12Rβ1 and IL-12Rβ2 expression.

Main Results:

  • IL-12 p40(2) activated ERK and p38 MAPK pathways.
  • ERK pathway mediated p40(2)-induced iNOS via C/EBP beta, while p38 pathway involved both NF-κB and C/EBP beta.
  • p40(2) induced iNOS via IL-12Rβ1, involving ERK, p38, NF-κB, and C/EBP beta.
  • IL-12 p70-induced iNOS expression required both IL-12Rβ1 and IL-12Rβ2, with distinct roles in activating NF-κB, C/EBP beta, and GAS.

Conclusions:

  • Delineated distinct signaling pathways for IL-12 p40(2) and IL-12 p70 in microglia.
  • Identified a novel role for IL-12Rβ1 in mediating p40(2)-induced iNOS expression.
  • Highlighted the differential involvement of IL-12Rβ1 and IL-12Rβ2 in IL-12-driven microglial iNOS production, relevant to neuroinflammatory diseases.

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