title: Cinobufagin Modulates Human Innate Immune Responses and Triggers Antibacterial Activity.
abstract: The traditional Chinese medicine Chan-Su is widely used for treatment of cancer and cardiovascular diseases, but also as a remedy for infections such as furunculosis, tonsillitis and acute pharyngitis. The clinical use of Chan-Su suggests that it has anti-infective effects, however, the mechanism of action is incompletely understood. In particular, the effect on the human immune system is poorly defined. Here, we describe previously unrecognized immunomodulatory activities of cinobufagin (CBG), a major bioactive component of Chan-Su. Using human monocyte-derived dendritic cells (DCs), we show that LPS-induced maturation and production of a number of cytokines was potently inhibited by CBG, which also had a pro-apoptotic effect, associated with activation of caspase-3. Interestingly, CBG triggered caspase-1 activation and significantly enhanced IL-1β production in LPS-stimulated cells. Finally, we demonstrate that CBG upregulates gene expression of the antimicrobial peptides (AMPs) hBD-2 and hBD-3 in DCs, and induces secretion of HNP1-3 and hCAP-18/LL-37 from neutrophils, potentiating neutrophil antibacterial activity. Taken together, our data indicate that CBG modulates the inflammatory phenotype of DCs in response to LPS, and triggers an antibacterial innate immune response, thus proposing possible mechanisms for the clinical effects of Chan-Su in anti-infective therapy.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.|Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Xie
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Laura
authors.initials: L
authors.lastname: Spelmink
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Mario
authors.initials: M
authors.lastname: Codemo
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Karthik
authors.initials: K
authors.lastname: Subramanian
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Katrin
authors.initials: K
authors.lastname: Pütsep
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.|Department of Clinical Microbiology, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Henriques-Normark
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Olliver
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002018:Bufanolides / Q000494:pharmacology*; D020170:Caspase 1 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D007155:Immunologic Factors / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D023181:Antimicrobial Cationic Peptides; D002018:Bufanolides; D016207:Cytokines; D007155:Immunologic Factors; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C095591:chan su; D053148:Caspase 3; D020170:Caspase 1; C002471:cinobufagin