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| Kofi... |
 Posted: Thu Oct 29, 2009 9:10 pm |
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J Biol Chem. 2009 Aug 14;284(33):21810-27. Epub 2009 Jun 16.
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.
Chakraborty K, Maity PC, Sil AK, Takeda Y, Das S.
Department of Clinical Medicine, National Institute of Cholera and
Enteric Diseases, P-33 C.I.T. Road, Scheme XM, Beliaghata, Kolkata
700010, India.
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.
Publication Types:
* Research Support, Non-U.S. Gov't
PMID: 19531482 |
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