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Isolation, Transfection, and Culture of Primary Human Monocytes
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Isolation, Transfection, and Culture of Primary Human Monocytes

Published on: December 16, 2019

Human cytomegalovirus induces TLR4 signaling components in monocytes altering TIRAP, TRAM and downstream

Kok-Hooi Yew1, Cory Carpenter, R Scott Duncan

  • 1Pediatric Infectious Disease, Children's Mercy Hospitals, Kansas City, Missouri, United States of America. hyew@kumc.edu

Plos One
|September 13, 2012
PubMed

Insights

Human cytomegalovirus (HCMV) triggers innate immune responses in monocytes via Toll-like receptor 4 (TLR4)/MD2/CD14. This complex influences IL-6 and IL-8 production through TIRAP and TRAM signaling pathways.

Area of Science:

  • Immunology
  • Molecular Biology

Background:

  • Primary human cytomegalovirus (HCMV) activates innate immune responses in monocytes via Toll-like receptor (TLR) pathways.
  • Lipopolysaccharide (LPS) recognition by TLR4/MD2/CD14 involves differential signaling through TIRAP-TRAF6 and TRAM-TRIF, impacting cytokine gene activation.

Purpose of the Study:

  • To investigate the roles of the TLR4/MD2/CD14 complex and its adaptor proteins TIRAP and TRAM in regulating monocyte responses to HCMV.
  • To elucidate the signaling pathways governing cytokine production, specifically IL-6, IL-8, and IFN-β, during HCMV infection.

Main Methods:

  • Utilized monocytes and primary HCMV strains.
  • Employed inhibitory studies with antisense oligonucleotides and neutralizing antibodies.
  • Assessed mRNA expression of TIRAP and TRAM.
  • Investigated the effects of exogenous recombinant CD14.

Main Results:

  • The TLR4/MD2/CD14 complex significantly contributes to HCMV-induced signaling and cytokine production in monocytes.
  • IL-6 and IL-8 induction correlated with increased TIRAP and decreased TRAM mRNA levels.
  • Reduced TRAM expression may activate a compensatory pathway for robust IFN response when TIRAP signaling is blocked.
  • IL-6 induction by TLR4/MD2 is crucial for endogenous CD14 activation, which synergizes with TLR4/MD2 for IL-8 expression.
  • Exogenous CD14 enhanced innate immune responses, promoting IL-8 and IFN-β production via TLR4- and TLR9-dependent pathways.

Conclusions:

  • The TLR4/MD2/CD14 complex plays a critical role in mediating monocyte responses to HCMV.
  • Differential regulation of TIRAP and TRAM adaptors influences the balance of pro-inflammatory and antiviral cytokine production.
  • CD14 acts as a key co-factor in TLR4-mediated signaling for IL-8 production and can potentiate innate immunity through TLR4 and TLR9 pathways.

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