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KLF6 and HSF4 transcriptionally regulate multidrug resistance transporters during inflammation

Emmanuel A Ho1, Micheline Piquette-Miller

  • 1Department of Pharmaceutical Sciences, University of Toronto, Leslie Dan Faculty of Pharmacy, 144 College Street, Toronto, Ont., Canada M5S 3M2.

Biochemical and Biophysical Research Communications
|January 2, 2007
PubMed

Insights

This study identifies KLF6 and HSF4 as key regulators of drug transporter genes mdr1b and mrp3 during inflammation. These transcription factors influence gene expression in response to endotoxin and inflammatory cytokines.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Hepatology

Background:

  • Hepatic drug efflux transporter expression, including mdr1b (Abcb1b) and mrp3 (Abcc3), is altered by endotoxin-induced inflammation in rats.
  • Understanding the transcriptional regulation of these transporters is crucial for managing drug disposition during inflammatory conditions.

Purpose of the Study:

  • To identify novel cis-elements and transcription factors regulating the expression of rat mdr1b and mrp3 genes during inflammation.
  • To elucidate the specific roles of identified regulatory elements in response to inflammatory stimuli like IL-1beta, TNF-alpha, and endotoxin.

Main Methods:

  • Promoter-reporter assays were used to analyze the function of identified cis-elements on rat mdr1b and mrp3 promoters.
  • Site-directed mutagenesis was employed to delete specific transcription factor binding sites (KLF6, C/EBPbeta, HSF4).
  • Gene expression was assessed under basal conditions and following stimulation with inflammatory mediators (IL-1beta, TNF-alpha, endotoxin).

Main Results:

  • A novel KLF6 cis-element on the rat mdr1b promoter was identified, crucial for basal activity and induction by IL-1beta and endotoxin.
  • KLF6 acted as a negative regulator, inhibiting TNF-alpha-mediated induction of mdr1b.
  • Novel C/EBPbeta and HSF4 binding sites were found on the rat mrp3 promoter; HSF4 element deletion increased mrp3 activity with TNF-alpha.
  • Endotoxin significantly impacted mrp3 transcriptional activity only in constructs with both C/EBPbeta and HSF4 elements deleted.

Conclusions:

  • KLF6 and HSF4 are identified as stimuli-specific regulatory elements involved in controlling rat mdr1b and mrp3 gene expression.
  • These findings suggest a significant role for KLF6 and HSF4 in the transcriptional regulation of drug transporters during both health and disease states.
  • The differential regulation by KLF6 and HSF4 highlights their importance in the dynamic changes of drug transporter expression during inflammation.

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