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

Jongdae Lee, Masaaki Hayashi, Jeng Fan Lo, Colleen Fearns, Wen Ming Chu, Yunping Luo, Rong Xiang, Tsung Hsien Chuang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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-κB (nuclear factor κB)-binding motif in this region, and this activation could be blocked by mutation of the NF-κB binding site or addition of NF-κB inhibitors. Further studies showed that pretreatment of the Hep3B hepatocytes with TNF-α (tumour necrosis factor-α) 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-κB-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.

Original languageEnglish
Pages (from-to)301-310
Number of pages10
JournalBiochemical Journal
Volume421
Issue number2
DOIs
StatePublished - 15 Jul 2009

Keywords

  • Cell activation
  • Gene regulation
  • Inflammation
  • Interferon regulatory factor
  • Nuclear factor-κB (NF-κB)
  • Toll-like receptor (TLR)

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