Nuclear factor kappaB (NF-kappaB) activation primes cells to a pro-inflammatory polarized response to a Toll-like receptor 7 (TLR7) agonist

Biochem J. 2009 Jun 26;421(2):301-10. doi: 10.1042/BJ20090013.

Abstract

TLR7 (Toll-like receptor 7) mediates anti-viral immunity by recognizing ssRNA (single-stranded RNA) viruses. Small-molecular-mass TLR7 agonists have been approved, or are being evaluated, for treatment of cancers or infectious diseases. Although TLR7 is predominantly expressed in a restricted set of immune cell types, including pDCs (plasmacytoid dendritic cells), it is also expressed in non-native expressing cells (e.g. hepatocytes) under certain circumstances. To elucidate the molecular basis of TLR7 induction by pro-inflammatory stimulation and the subsequent cellular responses in these non-native TLR7-expressing cell types, we first cloned and characterized the 5'-promoter region of TLR7. The proximal region of this promoter drives the transcription of the TLR7 gene. Pro-inflammatory stimuli activated TLR 7 transcription via a NF-kappaB (nuclear factor kappaB)-binding motif in this region, and this activation could be blocked by mutation of the NF-kappaB binding site or addition of NF-kappaB inhibitors. Further studies showed that pretreatment of the Hep3B hepatocytes with TNF-alpha (tumour necrosis factor-alpha) or IL-1 (interleukin-1) rendered them responsive to TLR7 activation by a TLR7 agonist. However, distinct from TLR7 activation in pDCs, which respond to stimulation with Th1 polarized cytokine production, TLR7 induction by pro-inflammatory signals in hepatocytes reconstitutes the NF-kappaB-dependent cascade but not the IRF7 (interferon regulatory factor 7)-dependent cascade, resulting in a pro-inflammatory polarized response rather than a Th1 polarized response. These results indicate that inflammatory stimulation is capable of priming cells to respond to TLR7 agonist with an immune response that differs from that in native TLR7-expressing cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Humans
  • Inflammation Mediators / pharmacology*
  • Interleukin-1 / metabolism
  • Molecular Sequence Data
  • NF-kappa B / metabolism*
  • Promoter Regions, Genetic
  • Toll-Like Receptor 7 / agonists*
  • Toll-Like Receptor 7 / biosynthesis
  • Toll-Like Receptor 7 / genetics*
  • Transcriptional Activation*
  • Transfection
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Inflammation Mediators
  • Interleukin-1
  • NF-kappa B
  • Toll-Like Receptor 7
  • Tumor Necrosis Factor-alpha