title: Mycobacterium tuberculosis increases IP-10 and MIG protein despite inhibition of IP-10 and MIG transcription.
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).
authors.affiliation: Denver Veterans Affair Medical Center, University of Colorado Denver, Aurora, CO, United States. baix@njhealth.org
authors.forename: Xiyuan
authors.initials: X
authors.lastname: Bai
authors.forename: Kathryn
authors.initials: K
authors.lastname: Chmura
authors.forename: Alida R
authors.initials: AR
authors.lastname: Ovrutsky
authors.forename: Russell P
authors.initials: RP
authors.lastname: Bowler
authors.forename: Robert I
authors.initials: RI
authors.lastname: Scheinman
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Oberley-Deegan
authors.forename: Haiying
authors.initials: H
authors.lastname: Liu
authors.forename: Shaobin
authors.initials: S
authors.lastname: Shang
authors.forename: Diane
authors.initials: D
authors.lastname: Ordway
authors.forename: Edward D
authors.initials: ED
authors.lastname: Chan
mesh_terms: D015152:Blotting, Northern; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D054370:Chemokine CXCL9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000235:genetics; D014376:Tuberculosis / Q000235:genetics*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C114753:CXCL10 protein, human; C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D016328:NF-kappa B; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases