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Nuclear factor kappaB (NF-kappaB) activation primes cells to a pro-inflammatory polarized response to a Toll-like

Jongdae Lee1, Masaaki Hayashi, Jeng-Fan Lo

  • 1Department of Medicine, University of California San Diego, La Jolla, CA 92093-0663, USA.

The Biochemical Journal
|May 12, 2009
PubMed

Insights

Inflammatory signals can induce Toll-like receptor 7 (TLR7) expression in non-immune cells like hepatocytes. This priming leads to a pro-inflammatory response upon TLR7 activation, differing from the Th1 response seen in immune cells.

Area of Science:

  • Immunology
  • Molecular Biology

Background:

  • Toll-like receptor 7 (TLR7) is crucial for antiviral immunity, primarily expressed in plasmacytoid dendritic cells (pDCs).
  • TLR7 agonists are explored for cancer and infectious disease treatments.
  • TLR7 can be expressed in non-native cells, such as hepatocytes, under inflammatory conditions.

Purpose of the Study:

  • To investigate the molecular mechanisms of TLR7 induction by pro-inflammatory stimuli in non-native expressing cells.
  • To characterize the cellular responses to TLR7 activation in these primed cells.

Main Methods:

  • Cloning and characterization of the TLR7 5'-promoter region.
  • Analysis of NF-kappaB (nuclear factor kappaB) binding motifs and their role in TLR7 transcription.
  • Pretreatment of Hep3B hepatocytes with TNF-alpha (tumour necrosis factor-alpha) or IL-1 (interleukin-1) followed by TLR7 agonist stimulation.
  • Assessment of cytokine production and signaling pathway activation (NF-kappaB and IRF7/interferon regulatory factor 7).

Main Results:

  • Pro-inflammatory stimuli activate TLR7 transcription through an NF-kappaB-binding motif in its promoter.
  • Hepatocytes pretreated with TNF-alpha or IL-1 become responsive to TLR7 agonists.
  • TLR7 activation in primed hepatocytes induces an NF-kappaB-dependent, pro-inflammatory response, distinct from the Th1-polarized cytokine production observed in pDCs.
  • The IRF7-dependent cascade is not activated in primed hepatocytes.

Conclusions:

  • Inflammatory stimulation primes non-native TLR7-expressing cells, like hepatocytes, to respond to TLR7 agonists.
  • This response is characterized by NF-kappaB activation and pro-inflammatory cytokine release, differing significantly from the Th1-polarized response in pDCs.
  • Understanding these distinct immune responses is vital for developing targeted therapies using TLR7 agonists.

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