title: Modulation of cytokine production and enhancement of cell viability by TLR7 and TLR9 ligands during anthrax infection of macrophages.
abstract: Inhalation of Bacillus anthracis, a bioterrorism agent, results in a high mortality rate despite appropriate antibiotic therapy. Macrophages appear to be a key factor in B. anthracis pathogenesis. The burst of pro-inflammatory cytokines from macrophages could be a major cause of death in anthrax. However, preactivation of Toll-like receptors (TLRs) could modify the host response. TLR ligands stimulate the release of activating cytokines but may also down-modulate the subsequent deleterious cytokine response to pathogens. We developed a cell culture model to measure macrophage responses to B. anthracis spores and bacilli. We found that germination from spores to bacilli produced a substantial stimulus for the secretion of the cytokines IL-6, TNF-alpha, IL-10, and IL-12 p40. Our studies showed that pretreatment of mouse macrophages with the TLR9 ligand ISS-1018, or the TLR7 ligands R-848 and IT-37, results in a substantial decrease in the subsequent secretion of IL-6 and TNF-alpha in response to B. anthracis infection of macrophages. Furthermore, the TLR7 and TLR9 ligands significantly decreased anthrax-induced cytotoxicity in the macrophages. These findings suggest that TLR ligands may contribute to the enhancement of innate immunity in B. anthracis infection by suppressing potentially deleterious pro-inflammatory cytokine responses and by improving macrophage viability.
authors.affiliation: Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0640, USA. msabet@ucsd.edu
authors.forename: Mojgan
authors.initials: M
authors.lastname: Sabet
authors.forename: Howard B
authors.initials: HB
authors.lastname: Cottam
authors.forename: Donald G
authors.initials: DG
authors.lastname: Guiney
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D000881:Anthrax / Q000276:immunology; D001408:Bacillus anthracis / Q000276:immunology* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D008024:Ligands; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008805:Mice, Inbred A; D013171:Spores, Bacterial / Q000276:immunology / Q000502:physiology; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000378:metabolism*
chemical_list: C513038:2-(4-amino-2-(ethoxymethyl)-1H-imidazo(4,5-c)quinolin-1-yl)ethanol; D000634:Aminoquinolines; D016207:Cytokines; D007093:Imidazoles; D008024:Ligands; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; C402365:resiquimod