title: Pathways of IL-1β secretion by macrophages infected with clinical Mycobacterium tuberculosis strains.
abstract: The pro-inflammatory cytokine IL-1β is a key mediator of inflammation and plays an important role in the host resistance to Mycobacterium tuberculosis infections. To date, most studies have examined the mechanisms of IL-1β secretion using laboratory strains of M. tuberculosis and the findings may not be widely applicable to contemporary clinical strains. Here, we investigated the primary pathways of IL-1β secretion in macrophages infected with a panel of 17 clinical M. tuberculosis isolates, representing Euro-American, Indo-Oceanic and East-Asian/Beijing lineages. Our aim was to dissect the pathways involved in M. tuberculosis induced IL-1β secretion and to determine whether they are common to all clinical isolates. We found that the isolates were capable of eliciting variable concentrations of IL-1β from infected murine macrophages, but this phenomenon could not be attributed to differential IL-1β mRNA transcription or pro-IL-1β accumulation. We demonstrate that viable bacteria are required to induce IL-1β secretion from macrophages, but IL-1β secretion was only partially abrogated by caspase-1 inhibition. Almost complete IL-1β secretion inhibition was produced with combined caspase-1 and some serine protease inhibitors. Taken together, these findings demonstrate that clinical strains of M. tuberculosis employ a unique caspase-1 independent pathway to stimulate IL-1β secretion from macrophages.
authors.affiliation: MRC Centre for Molecular Bacteriology and Infection, Department of Medicine, Imperial College London, South Kensington Campus, London SW7 2AZ, UK. n.krishnan@imperial.ac.uk
authors.forename: Nitya
authors.initials: N
authors.lastname: Krishnan
authors.forename: Brian D
authors.initials: BD
authors.lastname: Robertson
authors.forename: Guy
authors.initials: G
authors.lastname: Thwaites
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D020170:Caspase 1 / Q000276:immunology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000276:immunology; D005260:Female; D005838:Genotype; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000382:microbiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000145:classification / Q000187:drug effects / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D012333:RNA, Messenger / Q000235:genetics; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D013045:Species Specificity; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D014774:Virulence / Q000235:genetics / Q000276:immunology
chemical_list: D053583:Interleukin-1beta; D012333:RNA, Messenger; D015842:Serine Proteinase Inhibitors; D020170:Caspase 1
keywords: Caspase-1; Interleukin-1β; Macrophages; Mycobacteria; Serine proteases