title: Mechanism of regulation of Na-H exchanger in inflammatory bowel disease: role of TLR-4 signaling mechanism.
abstract: OBJECTIVE
  We investigated the role of toll-like receptor-4 (TLR-4) signal transduction in the regulation of Na-H exchanger-1 isoform (NHE-1) in ulcerative colitis (UC).
  
  
  METHODS
  Colonic biopsies from control and UC patients were selected from four groups: controls (group 1), untreated UC patients (group 2), UC patients treated with 5'-aminosalicylic acid (5'-ASA) plus steroid (group 3), and UC patients treated with 5'-ASA plus azathioprine (AZA) (group 4). Patients presenting with abdominal pain (n = 13) and a normal colon on endoscopy served as controls. NHE-1, TLR-4, MyD88, NFkB and actin protein levels were estimated using Western blot analysis and sodium pump activity (PNPase) by a spectrophotometeric method. Myeloperoxidase (MPO) activity and histologic evaluation confirmed inflammation.
  
  
  RESULTS
  PNPase activity decreased significantly (P < 0.05) in the untreated UC patients as compared to the controls or treated UC groups 3 and 4. There was a significant decrease of NHE-1 and a significant increase (P < 0.05) of TLR-4, MyD88 and NFkB protein levels in the untreated UC or 5'-ASA plus steroid treated UC patients as compared to the controls. NHE-1, TLR-4, MyD88 and NFkB protein levels were not significantly different in 5'-ASA plus AZA treated biopsies as compared to controls. The level of actin remained unaltered. Inflammatory cells' infiltration and MPO activity increased significantly in the untreated UC, but was significantly lower in the treated UC groups 3 and 4 (P < 0.05).
  
  
  CONCLUSIONS
  These findings suggest that NHE-1 in UC is regulated by NFkB induced through TLR-4 and MyD88 signaling mechanism. These findings identify TLR-4 as a putative therapeutic target for IBD.
authors.affiliation: Department of Medicine, Faculty of Medicine, Kuwait University, Safat, Kuwait.
authors.forename: Iqbal
authors.initials: I
authors.lastname: Siddique
authors.forename: Islam
authors.initials: I
authors.lastname: Khan
mesh_terms: D000328:Adult; D003093:Colitis, Ulcerative / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D017923:Sodium-Hydrogen Exchangers; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4