Essential role of STAT-3 dependent NF-κB activation on IL-6-mediated downregulation of hepatic transporters

Eur J Pharm Sci. 2020 Feb 15;143:105151. doi: 10.1016/j.ejps.2019.105151. Epub 2019 Nov 15.

Abstract

IL-6 markedly decreases the expression of numerous hepatic transporters. We previously demonstrated that IL-6-mediated downregulation of transporters occurs through STAT3, with partial involvement of PXR. However, while IL-6-mediated induction of STAT3 occurs rapidly, repression of transporter expression is not observed until 6 h post-treatment. This temporal mismatch suggested that the downregulation of transporters following IL-6 at 6 h might require additional signaling downstream of STAT3. Since NF-κB has been implicated in endotoxin-mediated downregulation of transporters, we hypothesized that NF-κB may be similarly involved in suppressing transporter expression following IL-6. Our objective was to investigate whether IL-6-mediated changes in transporter expression occur through STAT3-dependent NF-κB activation, and whether PXR is involved. PXR null (-/-) or wild type (+/+) mice were pre-dosed with the NF-κB inhibitor PHA408 or vehicle 30 min prior to receiving a single dose of IL-6 or saline. Mice were euthanized after 6 h and transporter expression was analyzed using qRT-PCR. IL-6 imposed downregulation of Abcb1a, Abcb1b, Abcc3, Abcg2 and Cyp3a11 in both PXR (+/+) and PXR (-/-) mice, while downregulation of Abcb11, Abcc2, Slc10a1, and Slco2b1 was only significant in PXR (+/+) mice. PHA408 pretreatment fully inhibited NF-κB activation in PXR (+/+) but only partially inhibited NF-κB in PXR (-/-). Inhibition of NF-κB attenuated IL-6-mediated changes in transporters in PXR (+/+) mice. Transient transfection assays did not detect significant activation of human or mouse PXR by PHA408. Our findings suggest that IL-6 imposes significant downregulation of numerous ABC and SLC transporters in the liver via collaborative STAT3/NF-κB activation. Since drug transporters play an integral role in the pharmacokinetics of numerous clinically relevant drugs, understanding the signaling pathways involved in transporter regulation during inflammation will contribute to a better understanding of drug-disease interactions.

Keywords: Il-6; Inflammation; NF-κB; Nuclear receptors; PXR; Transporters.

MeSH terms

  • Animals
  • Down-Regulation
  • Interleukin-6 / blood*
  • Liver / metabolism*
  • Male
  • Membrane Transport Proteins / genetics*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / metabolism*
  • Pregnane X Receptor / genetics
  • Pregnane X Receptor / metabolism
  • STAT3 Transcription Factor / metabolism

Substances

  • Interleukin-6
  • Membrane Transport Proteins
  • NF-kappa B
  • Nr1i2 protein, mouse
  • Pregnane X Receptor
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • interleukin-6, mouse