title: Host defense peptide LL-37, in synergy with inflammatory mediator IL-1beta, augments immune responses by multiple pathways.
abstract: The human cathelicidin LL-37 is a cationic host defense peptide and serves as an important component of innate immunity. It has been demonstrated to be a multifunctional modulator of innate immune responses, although the mechanism(s) underlying this have not been well characterized. In this study, it was demonstrated that LL-37 synergistically enhanced the IL-1beta-induced production of cytokines (IL-6, IL-10) and chemokines such as macrophage chemoattractant proteins (MCP-1, MCP-3) in human PBMC, indicating a role in enhancing certain innate immune responses. Similarly, LL-37 synergistically enhanced chemokine production in the presence of GM-CSF, but IFN-gamma, IL-4, or IL-12 addition led to antagonism, indicating that the role of LL-37 in reinforcing specific immune responses is selective and restricted to particular endogenous immune mediators. The inhibition of G protein-coupled receptors and PI3K substantially suppressed the ability of IL-1beta and LL-37 to synergistically enhance the production of chemokine MCP-3. Consistent with this, the combination of IL-1beta and LL-37 enhanced the activation/phosphorylation of kinase Akt and the transcription factor CREB. The role of transcription factor NF-kappaB was revealed through the demonstration of enhanced phosphorylation of IkappaBalpha and the consequent nuclear translocation of NF-kappaB subunits p50 and p65, as well as the antagonistic effects of an inhibitor of IkappaBalpha phosphorylation. These results together indicate that the human host defense peptide LL-37 can work in synergy with the endogenous inflammatory mediator IL-1beta to enhance the induction of specific inflammatory effectors by a complex mechanism involving multiple pathways, thus reinforcing certain innate immune responses.
authors.affiliation: Department of Microbiology and Immunology, Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jie
authors.initials: J
authors.lastname: Yu
authors.forename: Neeloffer
authors.initials: N
authors.lastname: Mookherjee
authors.forename: Kathleen
authors.initials: K
authors.lastname: Wee
authors.forename: Dawn M E
authors.initials: DM
authors.lastname: Bowdish
authors.forename: Jelena
authors.initials: J
authors.lastname: Pistolic
authors.forename: Yuexin
authors.initials: Y
authors.lastname: Li
authors.forename: Linda
authors.initials: L
authors.lastname: Rehaume
authors.forename: Robert E W
authors.initials: RE
authors.lastname: Hancock
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology / Q000502:physiology*; D054410:Chemokine CCL7 / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006801:Humans; D007249:Inflammation; D053583:Interleukin-1beta / Q000494:pharmacology / Q000502:physiology*; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D016328:NF-kappa B / Q000494:pharmacology / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; C515450:CCL7 protein, human; D054410:Chemokine CCL7; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D054804:Cathelicidins