Studies of patients with active
tuberculosis (TB) and infected healthy individuals have shown that
interferon (IFN)-gamma is present in sites of
Mycobacterium tuberculosis infection in comparable levels. This suggests that there is a deficiency in the macrophage response to IFN-gamma in TB patients. We used recombinant human IFN-gamma to stimulate adherent monocyte-derived macrophages from three groups of people: patients with active
tuberculosis (
TBP), their healthy household contacts (HHC) and healthy uninfected controls from the community (CC). We then evaluated the ability of the macrophages to inhibit the growth of M.
tuberculosis H37Rv as well as their
cytokine profile at early in
infection (48 h). After IFN-gamma treatment, macrophages of healthy individuals (HHC and CC) controlled M.
tuberculosis growth and produced mainly
nitric oxide (NO) and
interleukin (IL)-12p70, whereas
TBP macrophages did not kill M.
tuberculosis. Additionally,
TBP macrophages produced low levels of NO and IL-12p70 and high levels of tumour
necrosis factor (
TNF)-alpha and
IL-10.
Transforming growth factor (
TGF)-beta levels were similar among all three groups. M.
tuberculosis infection had little effect on the
cytokine response after IFN-gamma stimulus, but
infection alone induced more
IL-10 and
TGF-beta in
TBP macrophages. There were no differences in Stat1 nuclear translocation and
DNA binding between the groups. However, the phosphorylated Stat1 and c-Jun (AP-1) in
nuclear protein extracts was diminished in
TBP macrophages compared to macrophages of healthy individuals. These results indicate an impairment of Stat1-dependent and Stat1-independent IFN-gamma signalling in macrophages of people with active
tuberculosis, suggesting a different molecular regulation that could impact macrophage functionality and disease outcome.