Aryl hydrocarbon receptor activation synergistically induces lipopolysaccharide-mediated expression of proinflammatory chemokine (c-c motif) ligand 20

Tejas S. Lahoti, Jacob A. Boyer, Ann Kusnadi, Gulsum E. Muku, Iain A. Murray, Gary H. Perdew

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

The Ah receptor (AHR) is directly involved in the regulation of both innate and adaptive immunity. However, these activities are poorly understood at the level of gene regulation. The chemokine (c-c motif) ligand 20 (CCL20) plays a nonredundant role in the chemoattraction of C-C motif receptor 6 expressing cells (eg, T cells and others). A survey of promoter regions of chemokine genes revealed that there are several putative dioxin responsive elements in the mouse Ccl20 promoter. The addition of an AHR agonist along with lipopolysaccharide (LPS) to cultured primary peritoneal macrophages results in synergistic induction of both Ccl20 mRNA and protein, compared with each compound alone. Through the use of macrophage cultures derived from Ahr-/- and Ahrnls/nls mice, it was established that expression of the AHR and its ability to translocate into the nucleus are necessary for AHR ligand-mediated synergistic induction of Ccl20. Gel shift analysis determined that a potent tandem AHR binding site ~3.1 kb upstream from the transcriptional start site can efficiently bind the AHR/ARNT (aryl hydrocarbon receptor/AHR nuclear translocator) heterodimer upon activation with a number of AHR agonists. Furthermore, studies reveal that LPS increases AHR levels on the Ccl20 promoter while decreasing HDAC1 occupancy. The level of Ccl20 constitutive expression in the colon is greatly attenuated in Ahr-/- mice. These studies suggest that the presence of AHR ligands during localized inflammation may augment chemokine expression, thus participating in the overall response to pathogens.

Original languageEnglish (US)
Article numberkfv178
Pages (from-to)229-240
Number of pages12
JournalToxicological Sciences
Volume148
Issue number1
DOIs
StatePublished - Nov 2015

All Science Journal Classification (ASJC) codes

  • Toxicology

Fingerprint Dive into the research topics of 'Aryl hydrocarbon receptor activation synergistically induces lipopolysaccharide-mediated expression of proinflammatory chemokine (c-c motif) ligand 20'. Together they form a unique fingerprint.

  • Cite this