Impaired activation of Stat1 and c-Jun as a possible defect in macrophages of patients with active tuberculosis

Authors

  • H. Esquivel-Solís,

    1. Programa de Inmunología Molecular Microbiana. Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México,
    Search for more papers by this author
  • F. Quiñones-Falconi,

    1. Departamento de Microbiología Clínica, Instituto Nacional de Enfermedades Respiratorias, Tlalpan, Mexico City, Mexico
    Search for more papers by this author
  • A. Zarain-Herzberg,

    1. Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán and
    Search for more papers by this author
  • R. I. Amieva-Fernández,

    1. Programa de Inmunología Molecular Microbiana. Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México,
    Search for more papers by this author
  • Y. López-Vidal

    Corresponding author
    1. Programa de Inmunología Molecular Microbiana. Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México,
    Search for more papers by this author

Y. López-Vidal, Programa de Immunología Molecular Microbiana, 4° piso Edificio de Investigación, Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán 04510, Mexico City, Mexico.
E-mail: lvidal@servidor.unam.mx

Summary

Studies of patients with active tuberculosis (TB) and infected healthy individuals have shown that interferon (IFN)-γ is present in sites of Mycobacterium tuberculosis infection in comparable levels. This suggests that there is a deficiency in the macrophage response to IFN-γ in TB patients. We used recombinant human IFN-γ 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-γ 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)-α and IL-10. Transforming growth factor (TGF)-β levels were similar among all three groups. M. tuberculosis infection had little effect on the cytokine response after IFN-γ stimulus, but infection alone induced more IL-10 and TGF-β 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-γ signalling in macrophages of people with active tuberculosis, suggesting a different molecular regulation that could impact macrophage functionality and disease outcome.

Ancillary