Innate antimicrobial host defense in small intestinal Crohn's disease.
Paneth cells (PCs) are specialized epithelial cells predominantly found in the small intestinal crypts of Lieberkuehn. They produce different broad spectrum antimicrobial peptides most abundantly the alpha-defensins HD-5 and -6 (DEFA5 und DEFA6). Both these PC products show a specific reduction in small intestinal Crohn's disease (CD) - a form of inflammatory bowel disease (IBD). Their decrease is independent of current inflammation and an association with a NOD2 frameshift mutation has been demonstrated. More recently, another independent and even more frequent mechanism has been found which is linked to diminished levels of the Wnt pathway transcription factor TCF7L2 (also known as TCF4). Besides regulating the expression of HD-5 and HD-6 as TCF4 target genes, the Wnt pathway also orchestrates Paneth cell differentiation and maturation and controls stem cell maintenance in the small intestine. Besides NOD2 (which is predominantly expressed in PC) and ATG16L1 (inter alia important in the exocytosis of PC products), TCF4 is the third gene which is associated with small intestinal CD and Paneth cell antimicrobial function. Thus, Paneth cells seem to be key player emphazising a paramount importance of antimicrobial host defense in small intestinal CD pathogenesis.
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, D-70376 Stuttgart, Germany.
Maureen J
MJ
Koslowski
Julia
J
Beisner
Eduard F
EF
Stange
Jan
J
Wehkamp
D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis* / Q000494:pharmacology*; D000071183:Autophagy-Related Proteins; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000502:physiology; D002352:Carrier Proteins / Q000502:physiology; D003424:Crohn Disease / Q000276:immunology* / Q000382:microbiology*; D006801:Humans; D007113:Immunity, Innate; D007421:Intestine, Small / Q000276:immunology* / Q000382:microbiology*; D008954:Models, Biological; D053473:Nod2 Signaling Adaptor Protein / Q000502:physiology; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000502:physiology
C518959:ATG16L1 protein, human; D023181:Antimicrobial Cationic Peptides; D000071183:Autophagy-Related Proteins; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors