title: Inhibition of ex vivo proinflammatory cytokine secretion in fatal Mycobacterium tuberculosis infection.
abstract: Tuberculosis is characterized by fever, weight loss, a prolonged acute-phase protein response and granuloma formation. These characteristics may partly be due to action of proinflammatory cytokines tumour necrosis factor (TNF), IL-6 and IL-8. We investigated plasma concentrations of these cytokines before and after ex vivo lipopolysaccharide stimulation of whole blood leucocytes from 41 Zambian patients with tuberculosis, 32 of whom were also HIV+. Although patients had a reduced weight, were more anaemic and had higher erythrocyte sedimentation rate compared with controls (all P < 0.0005), clinical and laboratory measurements of disease state were similar in those who died and survivors. In contrast, plasma IL-6 and IL-8 concentrations were higher in patients who died (P < 0.05). There was no detectable cytokine mRNA in unstimulated leucocytes. There was reduced secretion of TNF (P < 0.005 at 2 h), IL-6 (P < 0.005 at 8 h) and IL-8 (P < 0.005 at 24 h) after ex vivo stimulation of whole blood leucocytes from patients who died compared with survivors. This was partly due to a soluble inhibitory factor present in plasma. The only additional effect of concurrent infection by HIV with Myco. tuberculosis was decreased IL-6 secretion following ex vivo stimulation of leucocytes. Reduced proinflammatory cytokine release may represent a critical impairment of host immune defences important in determining outcome in tuberculosis.
authors.affiliation: Division of Communicable Diseases, St. George's Hospital Medical School, London, UK.
authors.forename: J S
authors.initials: JS
authors.lastname: Friedland
authors.forename: J C
authors.initials: JC
authors.lastname: Hartley
authors.forename: C G
authors.initials: CG
authors.lastname: Hartley
authors.forename: R J
authors.initials: RJ
authors.lastname: Shattock
authors.forename: G E
authors.initials: GE
authors.lastname: Griffin
mesh_terms: D000328:Adult; D005260:Female; D006679:HIV Seropositivity / Q000150:complications; D006801:Humans; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism*; D016209:Interleukin-8 / Q000097:blood / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D008297:Male; D009169:Mycobacterium tuberculosis; D014376:Tuberculosis / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha