title: Bovine and human cathelicidin cationic host defense peptides similarly suppress transcriptional responses to bacterial lipopolysaccharide.
abstract: Genomic approaches can be exploited to expose the complexities and conservation of biological systems such as the immune network across various mammalian species. In this study, temporal transcriptional expression profiles were analyzed in human and bovine monocytic cells in response to the TLR-4 agonist, LPS, in the presence or absence of their respective host defense peptides. The cathelicidin peptides, human LL-37 and bovine myeloid antimicrobial peptide-27 (BMAP-27), are homologs, yet they have diverged notably in terms of sequence similarity. In spite of their low sequence similarities, both of these cathelicidin peptides demonstrated potent, antiendotoxin activity in monocytic cells at low, physiologically relevant concentrations. Microarray studies indicated that 10 ng/ml LPS led to the up-regulation of 125 genes in human monocytes, 106 of which were suppressed in the presence of 5 mug/ml of the human peptide LL-37. To confirm and extend these data, temporal transcriptional responses to LPS were assessed in the presence or absence of the species-specific host defense peptides by quantitative real-time PCR. The transcriptional trends of 20 LPS-induced genes were analyzed in bovine and human monocytic cells. These studies demonstrated conserved trends of gene responses in that both peptides were able to profoundly suppress many LPS-induced genes. Consistent with this, the human and bovine peptides suppressed LPS-induced translocation of NF-kappaB subunits p50 and p65 into the nucleus of monocytic cells. However, there were also distinct differences in responses to LPS and the peptides; for example, treatment with 5 mug/ml BMAP-27 alone tended to influence gene expression (RELA, TNF-alpha-induced protein 2, MAPK phosphatase 1/dual specificity phosphatase 1, IkappaBkappaB, NFkappaBIL1, TNF receptor-associated factor 2) to a greater extent than did the same amount of human LL-37. We hypothesize that the immunomodulatory effects of the species-specific host defense peptides play a critical role in regulating inflammation and represent an evolutionarily conserved mechanism for maintaining homeostasis, although the sequence divergence of these peptides is substantial.
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Neeloffer
authors.initials: N
authors.lastname: Mookherjee
authors.forename: Heather L
authors.initials: HL
authors.lastname: Wilson
authors.forename: Silvana
authors.initials: S
authors.lastname: Doria
authors.forename: Yurij
authors.initials: Y
authors.lastname: Popowych
authors.forename: Reza
authors.initials: R
authors.lastname: Falsafi
authors.forename: Jie Jessie
authors.initials: JJ
authors.lastname: Yu
authors.forename: Yuexin
authors.initials: Y
authors.lastname: Li
authors.forename: Sarah
authors.initials: S
authors.lastname: Veatch
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Roche
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Brown
authors.forename: Fiona S L
authors.initials: FS
authors.lastname: Brinkman
authors.forename: Karsten
authors.initials: K
authors.lastname: Hokamp
authors.forename: Andy
authors.initials: A
authors.lastname: Potter
authors.forename: Lorne A
authors.initials: LA
authors.lastname: Babiuk
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Griebel
authors.forename: Robert E W
authors.initials: RE
authors.lastname: Hancock
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000276:immunology / Q000494:pharmacology*; D002417:Cattle; D002460:Cell Line; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019143:Evolution, Molecular; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D015894:Genome, Human / Q000276:immunology; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology*; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects* / Q000276:immunology; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D008070:Lipopolysaccharides; D054804:Cathelicidins