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Antimicrobial Agents and Chemotherapy, December 2009, p. 5127-5133, Vol. 53, No. 12
0066-4804/09/$08.00+0     doi:10.1128/AAC.00818-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Phenylbutyrate Induces Antimicrobial Peptide Expression {triangledown}

Jonas Steinmann,1 Skarphédinn Halldórsson,1 Birgitta Agerberth,2 and Gudmundur H. Gudmundsson1*

Institute of Biology, University of Iceland, Reykjavik, Iceland,1 Medical Biophysics and Biochemistry, Karolinska Institutet, Stockholm, Sweden2

Received 18 June 2009/ Returned for modification 14 August 2009/ Accepted 4 September 2009

Antimicrobial peptides (AMPs) are important components of our first line of defense. Induction of AMPs such as LL-37 of the cathelicidin family might provide a novel approach in treating bacterial infections. In this study we identified 4-phenylbutyrate (PBA) as a novel inducer of AMP expression and investigated affected regulatory pathways. We treated various cell lines with PBA and assessed mRNA expression by real-time reverse transcriptase PCR (RT-PCR). Cathelicidin AMP (CAMP) gene expression was found to be upregulated in all four cell lines tested. Additionally, we found that the beta-defensin 1 gene was upregulated in the lung epithelial cell line VA10 while being downregulated in the monocytic cell line U937. Further we found that PBA induced CAMP gene expression synergistically with 1,25-dihydroxyvitamin D3 at both protein and mRNA levels. The general mechanism of induction of CAMP gene expression by PBA was found to be dependent on protein synthesis. Results from quantitative chromatin immunoprecipitation experiments challenge the common view that histone deacetylase inhibitors directly increase CAMP gene expression. Furthermore, we have demonstrated that inhibition of the mitogen-activated protein kinases MEK1/2 and c-Jun N-terminal kinase attenuate PBA-induced CAMP gene expression. Similarly, {alpha}-methylhydrocinnamate (ST7), an analogue of PBA, increases CAMP gene expression. Our findings contribute to understanding of the regulation of AMP expression and suggest that PBA and/or ST7 is a promising drug candidate for treatment of microbial infections by strengthening the epithelial antimicrobial barriers.

* Corresponding author. Mailing address: Biology Institute, University of Iceland, Sturlugata 7, 101 Reykjavik, Iceland. Phone: 354 525 5276. Fax: 354 525 4069. E-mail: ghrafn{at}hi.is

{triangledown} Published ahead of print on 21 September 2009.

Antimicrobial Agents and Chemotherapy, December 2009, p. 5127-5133, Vol. 53, No. 12
0066-4804/09/$08.00+0     doi:10.1128/AAC.00818-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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