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Infection and Immunity, February 2007, p. 820-829, Vol. 75, No. 2
0019-9567/07/$08.00+0     doi:10.1128/IAI.00602-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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{triangledown}

Edhyana Sahiratmadja,1,2 Bachti Alisjahbana,3 Tjitske de Boer,1 Iskandar Adnan,2 Anugrah Maya,4 Halim Danusantoso,4 Ronald H. H. Nelwan,5 Sangkot Marzuki,2 Jos W. M. van der Meer,6 Reinout van Crevel,6 Esther van de Vosse,7 and Tom H. M. Ottenhoff1*

Department of Immunohematology and Blood Transfusion,1 Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands,7 Eijkman Institute for Molecular Biology, Jakarta, Indonesia,2 Division of Tropical and Infectious Diseases, Department of Internal Medicine, Faculty of Medicine, University of Padjadjaran, Bandung, Indonesia,3 Indonesian Tuberculosis Control Association PPTI, Jakarta, Indonesia,4 Division of Tropical and Infection Diseases, Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia,5 Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands6

Received 13 April 2006/ Returned for modification 3 July 2006/ Accepted 18 November 2006

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-{gamma}R) 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-{gamma}R 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-{gamma}R 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-{gamma}R signaling may synergize in contributing to defective host control in active TB.

* Corresponding author. Mailing address: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. Phone: 31-71-5265128. Fax: 31-71-5216751. E-mail: t.h.m.ottenhoff{at}lumc.nl.

{triangledown} Published ahead of print on 4 December 2006.

Editor: J. L. Flynn

Infection and Immunity, February 2007, p. 820-829, Vol. 75, No. 2
0019-9567/07/$08.00+0     doi:10.1128/IAI.00602-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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