title: Dynamic changes in pro- and anti-inflammatory cytokine profiles and gamma interferon receptor signaling integrity correlate with tuberculosis disease activity and response to curative treatment.
abstract: Pro- and anti-inflammatory cytokines and their signaling pathways play key roles in protection from and pathogenesis of mycobacterial infection, and their balance and dynamic changes may control or predict clinical outcome. Peripheral blood cells' capacity to produce proinflammatory (tumor necrosis factor alpha [TNF-alpha], interleukin-12/23p40 [IL-12/23p40], and gamma interferon [IFN-gamma]) and anti-inflammatory (IL-10) cytokines in response to Mycobacterium tuberculosis or unrelated stimuli (lipopolysaccharide, phytohemagglutinin) was studied in 93 pulmonary tuberculosis (TB) patients and 127 healthy controls from Indonesia. Their cells' ability to respond to IFN-gamma was examined to investigate whether M. tuberculosis infection can also inhibit IFN-gamma receptor (IFN-gammaR) signaling. Although there was interindividual variability in the observed responses, the overall results revealed that M. tuberculosis-induced TNF-alpha and IFN-gamma levels showed opposite trends. Whereas TNF-alpha production was higher in active-TB patients than in controls, IFN-gamma production was strongly depressed during active TB, correlated inversely with TB disease severity, and increased during therapy. By contrast, mitogen-induced IFN-gamma production, although lower in patients than in controls, did not change during treatment, suggesting an M. tuberculosis-specific and reversible component in the depression of IFN-gamma. Depressed IFN-gamma production was not due to decreased IL-12/IL-23 production. Importantly, IFN-gamma-inducible responses were also significantly depressed during active TB and normalized during treatment, revealing disease activity-related and reversible impairment in IFN-gammaR signaling in TB. Finally, IFN-gamma/IL-10 ratios significantly correlated with TB cure. Taken together, these results show that M. tuberculosis-specific stimulation of IFN-gamma (but not TNF-alpha) production and IFN-gammaR signaling are significantly depressed in active TB, correlate with TB disease severity and activity, and normalize during microbiological TB cure. The depression of both IFN-gamma production and IFN-gammaR signaling may synergize in contributing to defective host control in active TB.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
authors.forename: Edhyana
authors.initials: E
authors.lastname: Sahiratmadja
authors.forename: Bachti
authors.initials: B
authors.lastname: Alisjahbana
authors.forename: Tjitske
authors.initials: T
authors.lastname: de Boer
authors.forename: Iskandar
authors.initials: I
authors.lastname: Adnan
authors.forename: Anugrah
authors.initials: A
authors.lastname: Maya
authors.forename: Halim
authors.initials: H
authors.lastname: Danusantoso
authors.forename: Ronald H H
authors.initials: RH
authors.lastname: Nelwan
authors.forename: Sangkot
authors.initials: S
authors.lastname: Marzuki
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.forename: Reinout
authors.initials: R
authors.lastname: van Crevel
authors.forename: Esther
authors.initials: E
authors.lastname: van de Vosse
authors.forename: Tom H M
authors.initials: TH
authors.lastname: Ottenhoff
mesh_terms: D000293:Adolescent; D000328:Adult; D000995:Antitubercular Agents / Q000627:therapeutic use; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D017471:Receptors, Interferon / Q000378:metabolism*; D015398:Signal Transduction; D013223:Statistics as Topic; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000276:immunology*; D000096743:Interferon gamma Receptor
chemical_list: D000995:Antitubercular Agents; D016207:Cytokines; D007371:Interferon-gamma; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor