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

Mycobacterium tuberculosis (MTB) has evolved methods to evade interferon-gamma (IFN gamma) mediated protection. We sought to determine the effect of MTB infection on expression of IFN gamma-inducible Protein 10 (IP-10) and Monokine Induced by IFN gamma (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 (STAT1 alpha) 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 (NF kappa B) and p38 mitogen-activated protein kinase (p38(mapk)) implicate these two signaling pathways in mediating the effect of MTB on the inhibition of IFN gamma-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 IFN gamma and MTB stimulation. MTB also inhibited IFN gamma induction of MIG mRNA but augmented MIG protein in primary human monocyte-derived macrophages. The synergy between MTB and IFN gamma in the induction of IP-10 and MIG protein appears to involve novel post-transcriptional events that incorporates non-canonical functions of NF kappa B and p38(mapk). Published by Elsevier Ltd.