Transcriptional regulation of the intestinal luminal Na⁺ and Cl⁻ transporters.

The epithelial apical membrane Na+/H+ exchangers [NHE (sodium hydrogen exchanger)2 and NHE3] and Cl−/HCO3− exchangers [DRA (down-regulated in adenoma) and PAT-1 (putative anion transporter 1)] are key luminal membrane transporters involved in electroneutral NaCl absorption in the mammalian intestine. During the last decade, there has been a surge of studies focusing on the short-term regulation of these electrolyte transporters, particularly for NHE3 regulation. However, the long-term regulation of the electrolyte transporters, involving transcriptional mechanisms and transcription factors that govern their basal regulation or dysregulation in diseased states, has only now started to unfold with the cloning and characterization of their gene promoters. The present review provides a detailed analysis of the core promoters of NHE2, NHE3, DRA and PAT-1 and outlines the transcription factors involved in their basal regulation as well as in response to both physiological (butyrate, protein kinases and probiotics) and pathophysiological (cytokines and high levels of serotonin) stimuli. The information available on the transcriptional regulation of the recently identified NHE8 isoform is also highlighted. Therefore the present review bridges a gap in our knowledge of the transcriptional mechanisms underlying the alterations in the gene expression of intestinal epithelial luminal membrane Na+ and Cl− transporters involved in electroneutral NaCl absorption. An understanding of the mechanisms of the modulation of gene expression of these transporters is important for a better assessment of the pathophysiology of diarrhoea associated with inflammatory and infectious diseases and may aid in designing better management protocols. Abbreviations: AP-2, activator protein 2; Caco-2 cell, human colon adenocarcinoma cell; CD, Crohn's disease; Cdx2, caudal-related homeobox 2; ChIP, chromatin immunoprecipitation; CLD, congenital chloride diarrhoea; CS, culture supernatants; DRA, down-regulated in adenoma; EGF, epidermal growth factor; Egr-1, early growth response protein 1; EMSA, electrophoretic mobility-shift assay; FABP, fatty-acid-binding protein; GAS, γ-activated site; GRE, glucocorticoid response element; HNF, hepatocyte nuclear factor; IBD, inflammatory bowel diseases; IEC, intestinal epithelial cell; IFNγ, interferon γ; IL, interleukin; Inr, initiator; IRF-1, interferon regulatory factor 1; ISRE, interferon-stimulated response element; JAK, Janus kinase; LA, Lactobacillus acidophilus; Luc, luciferase; MAPK, mitogen-activated protein kinase; MAZ, myc-associated zinc finger; MyoD, myogenic differentiation 1; Mzf1, myeloid zinc finger 1; NF-κB, nuclear factor κB; NHE, sodium hydrogen exchanger; hNHE, human NHE; Oct-1, octameric transcription factor 1; PAT-1, putative anion transporter 1; PKA, protein kinase A; PKC, protein kinase C; PRE, PMA response element; RIE cell, rat intestinal epithelial cell; rNHE, rat NHE; SCFA, short-chain fatty acid; siRNA, small interfering RNA; SLC, solute carrier; Sp1, specificity protein 1; STAT, signal transducer and activator of transcription; TIS, transcription initiation site; TNFα, tumour necrosis factor α; TRE, thyroid hormone receptor response element; UC, ulcerative colitis; USF, upstream stimulatory factor; UTR, untranslated region; YY1, Yin Yang 1