title: Differential regulation of human cathelicidin LL-37 by free fatty acids and their analogs.
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.
authors.affiliation: Department of Animal Science, Oklahoma State University, Stillwater, OK 74048, USA.
authors.forename: Weiyu
authors.initials: W
authors.lastname: Jiang
authors.forename: Lakshmi T
authors.initials: LT
authors.lastname: Sunkara
authors.forename: Xiangfang
authors.initials: X
authors.lastname: Zeng
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Deng
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Myers
authors.forename: Guolong
authors.initials: G
authors.lastname: Zhang
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics; D002087:Butyrates / Q000737:chemistry / Q000494:pharmacology*; D002208:Caproates / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006538:Heptanoic Acids / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007155:Immunologic Factors / Q000737:chemistry / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010421:Pentanoic Acids / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D054804:Cathelicidins
chemical_list: D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D002087:Butyrates; D002208:Caproates; D006538:Heptanoic Acids; D007155:Immunologic Factors; D010421:Pentanoic Acids; C037652:hexanoic acid; C038780:n-pentanoic acid; D054804:Cathelicidins
keywords: AP-1; Butyrate; CBP; CRAMP; CREB; CREB-binding protein; Cathelicidins; DMSO; HDACi; HDP; Heptanoate; Hexanoate; Host defense peptides; LCFA; LL-37; MAPK; MCFA; SCFA; Short-chain fatty acids; activator protein 1; cAMP; cAMP response element-binding protein; cathelicidin-related antimicrobial peptide; cyclic adenosine monophosphate; dimethyl sulfoxide; hBD; hCAP18; histone deacetylase inhibitor; host defense peptide; human cationic antimicrobial peptide of 18kDa; human β-defensin; long-chain fatty acid; medium-chain fatty acid; mitogen-activated protein kinase; short-chain fatty acid