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JNK1 activation mediates C5b-9-induced P0 mRNA instability and P0 gene expression in Schwann cells

Stefan David1, Sorana Hila, Matthew Fosbrink

  • 1Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Journal of the Peripheral Nervous System : JPNS
|March 8, 2006
PubMed

Insights

Complement C5b-9 reduces protein zero (P0) glycoprotein mRNA in Schwann cells by activating JNK1. This leads to P0 mRNA decay and repressed P0 gene transcription, impacting peripheral nerve myelin.

Area of Science:

  • Neuroscience
  • Immunology
  • Cell Biology

Background:

  • Protein zero (P0) glycoprotein is crucial for mammalian peripheral nervous system myelin.
  • Schwann cells produce P0, essential for nerve structure and function.
  • The complement cascade's terminal complex, C5b-9, can impact cellular processes.

Purpose of the Study:

  • To investigate the effect of sublytic C5b-9 on P0 gene expression in Schwann cells.
  • To elucidate the molecular mechanisms underlying C5b-9-mediated regulation of P0.
  • To determine the role of JNK1 signaling in C5b-9's impact on P0.

Main Methods:

  • Schwann cells were treated with sublytic C5b-9.
  • P0 mRNA levels were quantified using RT-PCR.
  • JNK1 activity and c-jun mRNA were measured.
  • Transcription inhibition assays with Actinomycin D were performed.
  • Luciferase reporter assays assessed P0 promoter activity.
  • Inhibitors of JNK signaling (L-JNKI1) were used.

Main Results:

  • Sublytic C5b-9 significantly decreased P0 mRNA expression (81% reduction within 6 hours).
  • C5b-9 induced a threefold increase in JNK1 activity and c-jun mRNA.
  • C5b-9 promoted P0 mRNA destabilization and repressed P0 gene transcription.
  • JNK1 activation was identified as the key mediator of these effects.
  • Inhibition of JNK1 prevented C5b-9-induced P0 downregulation.

Conclusions:

  • Complement C5b-9 negatively regulates P0 gene expression in Schwann cells.
  • JNK1 activation by C5b-9 leads to both enhanced mRNA decay and transcriptional repression of P0.
  • These findings reveal a novel mechanism by which complement activation affects peripheral nerve myelin integrity.

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