Differential regulation of human cathelicidin LL-37 by free fatty acids and their analogs |
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Affiliation: | 1. Department of Pathophysiology, Medical College of Qingdao University, Qingdao, Shandong 266021, PR China;2. Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, Shandong, PR China;1. Yale University School of Medicine, Department of Psychiatry, 300 George Street, New Haven, CT 06511, United States of America;2. VA Connecticut Healthcare System, 950 Campbell Ave, West Haven, CT 06516, United States of America;3. VISN I Mental Illness Research Education Clinical Center (MIRECC), 950 Campbell Ave, West Haven, CT 06516, United States of America |
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Abstract: | LL-37 is the single cathelicidin host defense peptide in humans with direct antimicrobial and immunomodulatory activities. Specific regulation of LL-37 synthesis has emerged as a novel non-antibiotic approach to disease control and prevention. Short-chain fatty acids, and butyrate in particular, were found recently to be strong inducers of LL-37 gene expression without causing inflammation. Here, we further evaluated the LL-37-inducing efficiency of a broad range of saturated free fatty acids and their derivatives in human HT-29 colonic epithelial cells and U-937 monocytic cells by real-time RT-PCR. Surprisingly, we revealed that valerate, hexanoate, and heptanoate with 5–7 carbons are more potent than 4-carbon butyrate in promoting LL-37 gene expression in both cell types. Free fatty acids with longer than 7 or shorter than 4 carbons showed only a marginal effect on LL-37 expression. Studies with a series of fatty acid derivatives with modifications in the aliphatic chain or carboxylic acid group yielded several analogs such as benzyl butyrate, trans-cinnamyl butyrate, glyceryl tributyrate, and phenethyl butyrate with a comparable LL-37-inducing activity to sodium butyrate. On the other hand, although reactive, the anhydride derivatives of short- and medium-chain fatty acids are as potent as their corresponding free acid forms in LL-37 induction. Thus, these newly identified free fatty acids and their analogs with a strong capacity to augment LL-37 synthesis may hold promise as immune boosting dietary supplements for antimicrobial therapy. |
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Keywords: | LL-37 Host defense peptides Cathelicidins Short-chain fatty acids Butyrate Hexanoate Heptanoate |
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