Nuclear factor kappaB (NF-kappaB) activation primes cells to a pro-inflammatory polarized response to a Toll-like receptor 7 (TLR7) agonist.
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.
Department of Medicine, University of California San Diego, La Jolla, CA 92093-0663, USA.
Jongdae
J
Lee
Masaaki
M
Hayashi
Jeng-Fan
JF
Lo
Colleen
C
Fearns
Wen-Ming
WM
Chu
Yunping
Y
Luo
Rong
R
Xiang
Tsung-Hsien
TH
Chuang
D001483:Base Sequence; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology*; D007375:Interleukin-1 / Q000378:metabolism; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics*; D015533:Transcriptional Activation; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018836:Inflammation Mediators; D007375:Interleukin-1; D016328:NF-kappa B; D051199:Toll-Like Receptor 7; D014409:Tumor Necrosis Factor-alpha