title: Cyclic AMP synergizes with butyrate in promoting β-defensin 9 expression in chickens.
abstract: Host defense peptides (HDP) have both microbicidal and immunomodulatory properties. Specific induction of endogenous HDP synthesis has emerged as a novel approach to antimicrobial therapy. Cyclic adenosine monophosphate (cAMP) and butyrate have been implicated in HDP induction in humans. However, the role of cAMP signaling and the possible interactions between cAMP and butyrate in regulating HDP expression in other species remain unknown. Here we report that activation of cAMP signaling induces HDP gene expression in chickens as exemplified by β-defensin 9 (AvBD9). We further showed that, albeit being weak inducers, cAMP agonists synergize strongly with butyrate or butyrate analogs in AvBD9 induction in macrophages and primary jejunal explants. Additionally, oral supplementation of forskolin, an adenylyl cyclase agonist in the form of a Coleus forskohlii extract, was found to induce AvBD9 expression in the crop of chickens. Furthermore, feeding with both forskolin and butyrate showed an obvious synergy in triggering AvBD9 expression in the crop and jejunum of chickens. Surprisingly, inhibition of the MEK-ERK mitogen-activated protein kinase (MAPK) pathway augmented the butyrate-FSK synergy, whereas blocking JNK or p38 MAPK pathway significantly diminished AvBD9 induction in chicken macrophages and jejunal explants in response to butyrate and FSK individually or in combination. Collectively, these results suggest the potential for concomitant use of butyrate and cAMP signaling activators in enhancing HDP expression, innate immunity, and disease resistance in both animals and humans.
authors.affiliation: Department of Animal Science, Oklahoma State University, Stillwater, OK 74078, USA.
authors.forename: Lakshmi T
authors.initials: LT
authors.lastname: Sunkara
authors.forename: Xiangfang
authors.initials: X
authors.lastname: Zeng
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Curtis
authors.forename: Guolong
authors.initials: G
authors.lastname: Zhang
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis; D002087:Butyrates / Q000378:metabolism*; D002478:Cells, Cultured; D002645:Chickens; D031330:Coleus; D005576:Colforsin / Q000008:administration & dosage / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D007583:Jejunum; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008264:Macrophages; D010936:Plant Extracts / Q000008:administration & dosage / Q000378:metabolism; D015398:Signal Transduction; D023083:beta-Defensins / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; D002087:Butyrates; D010936:Plant Extracts; D023083:beta-Defensins; D005576:Colforsin; D000242:Cyclic AMP; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases
keywords: 2′,5′-dideoxyadenosine; AP-1; Antibiotic alternative; AvBD9; BZB; Butyrate; CF; CRE; CRE-binding protein; CREB; CT; Chickens; Coleus forskohlii; DB-cAMP; DDA; Disease resistance; FSK; GAPDH; GTB; HBD1; HDACi; HDP; Host defense peptide; ICER; MAPK; PT; VDR; VDR response element; VRE; activator protein-1; avian β-defensin 9; benzyl butyrate; cAMP; cAMP response element; cAMP signaling; cholera toxin; cyclic adenosine monophosphate; dibutyryl-cAMP; forskolin; glyceraldehyde-3-phosphate dehydrogenase; glyceryl tributyrate; histone deacetylase inhibitor; host defense peptide; human β-defensin 1; inducible cAMP early repressor; mitogen-activated protein kinase; pertussis toxin; vitamin D receptor