Mycobacterium tuberculosis increases IP-10 and MIG protein despite inhibition of IP-10 and MIG transcription

Xiyuan Bai, Kathryn Chmura, Alida R. Ovrutsky, Russell P. Bowler, Robert I. Scheinman, Rebecca E. Oberley-Deegan, Haiying Liu, Shaobin Shang, Diane Ordway, Edward D. Chan

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Mycobacterium tuberculosis (MTB) has evolved methods to evade interferon-gamma (IFNγ) mediated protection. We sought to determine the effect of MTB infection on expression of IFNγ-inducible Protein 10 (IP-10) and Monokine Induced by IFNγ (MIG), two chemokines involved in host defense. MTB infection of THP-1 cells inhibited the transcription of IP-10 and MIG. A key mechanism for the inhibition is the disruption of binding of Signal Transduction and Activation of Transcription 1-alpha (STAT1α) to its cis-regulatory element, present in the 5′-flanking region of both IP-10 and MIG promoters. Use of inhibitors specific to the nuclear factor-kappa B (NFκB) and p38 mitogen-activated protein kinase (p38 mapk) implicate these two signaling pathways in mediating the effect of MTB on the inhibition of IFNγ-induced IP-10 and MIG mRNA expression. Interestingly, despite transcriptional inhibition, there was an unexpected increase in IP-10 and MIG protein production after combined IFNγ and MTB stimulation. MTB also inhibited IFNγ induction of MIG mRNA but augmented MIG protein in primary human monocyte-derived macrophages. The synergy between MTB and IFNγ in the induction of IP-10 and MIG protein appears to involve novel post-transcriptional events that incorporates non-canonical functions of NFκB and p38 mapk.

Original languageEnglish (US)
Pages (from-to)26-35
Number of pages10
JournalTuberculosis
Volume91
Issue number1
DOIs
StatePublished - Jan 2011

Keywords

  • IFNγ signaling
  • Macrophages
  • Nuclear factor-kappa B
  • Tuberculosis
  • p38 mitogen-activated protein kinase

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Microbiology (medical)
  • Infectious Diseases

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    Bai, X., Chmura, K., Ovrutsky, A. R., Bowler, R. P., Scheinman, R. I., Oberley-Deegan, R. E., Liu, H., Shang, S., Ordway, D., & Chan, E. D. (2011). Mycobacterium tuberculosis increases IP-10 and MIG protein despite inhibition of IP-10 and MIG transcription. Tuberculosis, 91(1), 26-35. https://doi.org/10.1016/j.tube.2010.11.005