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Published on: January 7, 2019

IFNgamma synergizes with IL-1beta to up-regulate MMP-9 secretion in a cellular model of central nervous system

James E Harris1, Marc Fernandez-Vilaseca, Paul T G Elkington

  • 1Department of Infectious Diseases and Immunity, Hammersmith Campus, Imperial College, Du Cane Rd., London, W12 0NN, UK.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|December 13, 2006
PubMed

Insights

Matrix metalloproteinase-9 (MMP-9) activity, crucial in central nervous system tuberculosis (CNS-TB), is unexpectedly increased by interferon-gamma (IFNγ) and interleukin-1 beta (IL-1β). This synergy, mediated by STAT-3, drives brain tissue destruction in CNS-TB.

Area of Science:

  • Neuroimmunology
  • Molecular Biology
  • Infectious Diseases

Background:

  • Matrix metalloproteinase-9 (MMP-9) activity is implicated in the pathogenesis of central nervous system tuberculosis (CNS-TB).
  • Interferon-gamma (IFNγ), a key cytokine in tuberculosis (TB), typically inhibits MMP-9 secretion.

Purpose of the Study:

  • To investigate the mechanisms underlying MMP-9 regulation in CNS-TB.
  • To identify key signaling pathways and mediators involved in MMP-9 activity during CNS-TB.

Main Methods:

  • Gelatin zymography and ELISA were used to measure MMP-9, TIMP-1, and TIMP-2 levels.
  • Monocytes infected with Mycobacterium tuberculosis (M. tb) were treated with IFNγ, IL-1β, and dexamethasone.
  • Western blotting and kinase inhibitors were employed to analyze signaling pathways, including MAPK, JAK-STAT.

Main Results:

  • IFNγ synergistically increased MMP-9 activity in M. tb-infected monocyte conditioned media (CoMTB), contrary to expectations.
  • Interleukin-1 beta (IL-1β) was identified as a critical mediator of this synergistic MMP-9 increase, which was abolished by dexamethasone.
  • The synergy involved p38 MAPK activation and was dependent on JAK-2 and STAT-3 phosphorylation, but not STAT-1 or Erk.
  • Tissue inhibitor of metalloproteinase (TIMP)-1 and -2 secretion was suppressed.

Conclusions:

  • Synergy between IL-1β and IFNγ signaling, mediated by STAT-3, is a key mechanism for up-regulating MMP-9 activity in CNS-TB.
  • This up-regulation of MMP-9 activity likely contributes significantly to brain tissue destruction in CNS-TB.
  • Targeting this pathway may offer therapeutic strategies for CNS-TB.

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