Downregulation of TACO gene transcription restricts mycobacterial entry/survival within human macrophages.
Recent reports have indicated that cholesterol-dependent association of tryptophan-aspartate containing coat protein (TACO) plays a crucial role in the entry/survival of Mycobacterium tuberculosis within human macrophages. Keeping this in view, the present study explored whether the molecules that have the ability to downregulate TACO gene transcription could also restrict entry/survival of mycobacteria within human macrophages. The study revealed that chenodeoxycholic acid (CDCA), either alone or in combination with retinoic acid (RA), had the inherent capacity to downregulate TACO gene transcription in a dose-dependent fashion. This result was in conformity with the existence of a functional FXR/RXR binding site analyzed in the regulatory region of the TACO gene. Furthermore, we demonstrate that the entry and intracellular survival of M. tuberculosis is significantly restricted in THP-1 macrophages exposed to CDCA/RA. On the basis of these findings, we propose that the CDCA/RA-dependent pathway may open a new possibility for the treatment of tuberculosis.
Anand
Paras K
PK
Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education and Research, Chandigarh 160 012, India.
Kaul
Deepak
D
D001483:Base Sequence; D002460:Cell Line; D002478:Cells, Cultured; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology* / Q000502:physiology*; D008840:Microfilament Proteins; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity*; D011506:Proteins / Q000235:genetics* / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear; D047488:Retinoid X Receptors / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology; D000099150:Receptor, Farnesoid X-Activated
D002635:Chenodeoxycholic Acid; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D008840:Microfilament Proteins; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014212:Tretinoin; D000099150:Receptor, Farnesoid X-Activated; C072061:coronin proteins