title: Bacterial exotoxins downregulate cathelicidin (hCAP-18/LL-37) and human beta-defensin 1 (HBD-1) expression in the intestinal epithelial cells.
abstract: Cathelicidin (hCAP-18/LL-37) and beta-defensin 1 (HBD-1) are human antimicrobial peptides (AMPs) with high basal expression levels, which form the first line of host defence against infections over the epithelial surfaces. The antimicrobial functions owe to their direct microbicidal effects as well as the immunomodulatory role. Pathogenic microorganisms have developed multiple modalities including transcriptional repression to combat this arm of the host immune response. The precise mechanisms and the pathogen-derived molecules responsible for transcriptional downregulation remain unknown. Here, we have shown that enteric pathogens suppress LL-37 and HBD-1 expression in the intestinal epithelial cells (IECs) with Vibrio cholerae and enterotoxigenic Escherichia coli (ETEC) exerting the most dramatic effects. Cholera toxin (CT) and labile toxin (LT), the major virulence proteins of V. cholerae and ETEC, respectively, are predominantly responsible for these effects, both in vitro and in vivo. CT transcriptionally downregulates the AMPs by activating several intracellular signalling pathways involving protein kinase A (PKA), ERK MAPKinase and Cox-2 downstream of cAMP accumulation and inducible cAMP early repressor (ICER) may mediate this role of CT, at least in part. This is the first report to show transcriptional repression of the AMPs through the activation of cellular signal transduction pathways by well-known virulence proteins of pathogenic microorganisms.
authors: National Institute of Cholera and Enteric Diseases, Kolkata, India.
authors: Krishnendu
authors: K
authors: Chakraborty
authors: Shubhamoy
authors: S
authors: Ghosh
authors: Hemanta
authors: H
authors: Koley
authors: Asish Kumar
authors: AK
authors: Mukhopadhyay
authors: Thandavarayan
authors: T
authors: Ramamurthy
authors: Dhira Rani
authors: DR
authors: Saha
authors: Debashis
authors: D
authors: Mukhopadhyay
authors: Swasti
authors: S
authors: Roychowdhury
authors: Takashi
authors: T
authors: Hamabata
authors: Yoshifumi
authors: Y
authors: Takeda
authors: Santasabuj
authors: S
authors: Das
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D001427:Bacterial Toxins / Q000633:toxicity*; D018938:Caco-2 Cells; D002772:Cholera Toxin / Q000633:toxicity*; D015536:Down-Regulation; D004768:Enterotoxins / Q000633:toxicity*; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology*; D029968:Escherichia coli Proteins / Q000633:toxicity*; D006801:Humans; D023083:beta-Defensins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D001427:Bacterial Toxins; C406407:DEFB1 protein, human; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D023083:beta-Defensins; D002772:Cholera Toxin; C027538:heat-labile enterotoxin, E coli; D054804:Cathelicidins