title: cAMP stringently regulates human cathelicidin antimicrobial peptide expression in the mucosal epithelial cells by activating cAMP-response element-binding protein, AP-1, and inducible cAMP early repressor.
abstract: Little is known about the regulation of the innate host defense peptide cathelicidin at the mucosal surfaces. Expression is believed to be transcriptionally regulated, and several cis-acting elements have been identified in the cathelicidin putative promoter. However, the trans-acting factors have not been clearly defined. We have recently reported that bacterial exotoxins suppress cathelicidin expression in sodium butyrate-differentiated intestinal epithelial cells (ECs), and this may be mediated through inducible cAMP early repressor. Here we have shown that cAMP-signaling pathways transcriptionally regulate cathelicidin expression in various ECs. cAMP-response element-binding protein (CREB) and AP-1 (activator protein-1) bind to the cathelicidin putative promoter in vitro. Additionally, transcriptional complexes containing CREB, AP-1, and cathelicidin upstream regulatory sequences are formed within ECs. We have also shown that these complexes may activate cathelicidin promoter and are required for its inducible expression in ECs. This is underscored by the fact that silencing of CREB and AP-1 results in failure of ECs to up-regulate cathelicidin, and hepatitis B virus X protein may use CREB to induce cathelicidin. On the other hand, inducible cAMP early repressor competes with CREB and AP-1 for binding to the cathelicidin promoter and represses transcription, thus functioning as a counter-regulatory mechanism. Finally, both CREB and AP-1 were shown to play major roles in the regulation of cathelicidin in sodium butyrate-differentiated HT-29 cells. This is the first report of a detailed mechanistic study of inducible cathelicidin expression in the mucosal ECs. At the same time, it describes a novel immunomodulatory function of cAMP.
authors.affiliation: Department of Clinical Medicine, National Institute of Cholera and Enteric Diseases, P-33 C.I.T. Road, Scheme XM, Beliaghata, Kolkata 700010.
authors.forename: Krishnendu
authors.initials: K
authors.lastname: Chakraborty
authors.affiliation: Department of Microbiology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata 700019.
authors.forename: Palash Chandra
authors.initials: PC
authors.lastname: Maity
authors.affiliation: Department of Microbiology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata 700019.
authors.forename: Alok Kumar
authors.initials: AK
authors.lastname: Sil
authors.affiliation: Collaborative Research Center of Okayama University for Infectious Diseases, National Institute of Cholera and Enteric Diseases, P-33 C.I.T. Road, Scheme XM, Beliaghata, Kolkata 700010, India.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Takeda
authors.affiliation: Department of Clinical Medicine, National Institute of Cholera and Enteric Diseases, P-33 C.I.T. Road, Scheme XM, Beliaghata, Kolkata 700010.
authors.forename: Santasabuj
authors.initials: S
authors.lastname: Das
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis* / Q000737:chemistry*; D018938:Caco-2 Cells; D054804:Cathelicidins; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism*; D051786:Cyclic AMP Response Element Modulator / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008957:Models, Genetic; D009092:Mucous Membrane / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism*
chemical_list: D023181:Antimicrobial Cationic Peptides; C497410:CREM protein, human; D054804:Cathelicidins; D017362:Cyclic AMP Response Element-Binding Protein; D018808:Transcription Factor AP-1; D051786:Cyclic AMP Response Element Modulator; D000242:Cyclic AMP