Synergistic action of vitamin D and retinoic acid restricts invasion of macrophages by pathogenic mycobacteria.
OBJECTIVE
Phagosomal maturation arrest is known to play a central role in the survival of pathogenic mycobacteria within macrophages. The maturation arrest of mycobacterial phagosome results from the retention of tryptophan-aspartate-containing coat protein (TACO) on this organelle, enabling successful replication of the pathogen. We have shown earlier that vitamin D(3) and retinoic acid (RA) down-regulate TACO gene transcription in a dose-dependent manner.


METHODS
In this study, we analyzed the promoter region of TACO gene using bioinformatics tools and observed that the vitamin D receptor (VDR)/retinoid-X-receptor (RXR) response sequence was highly functional. We also evaluated the effect of treatment with vitamin D(3)/RA on Mycobacterium tuberculosis entry and survival in cultured human macrophages.


RESULTS
TACO gene down-regulation observed with vitamin D(3)/RA treatment occurred through modulation of this gene via the VDR/RXR response sequence present in the promoter region of TACO gene. Treatment of macrophages with vitamin D(3)/RA allows maturation of mycobacterial phagosome, leading to degradation of the pathogen.


CONCLUSIONS
Our results elucidate the mechanism of TACO gene down-regulation observed with vitamin D(3)/RA. Furthermore, the results revealed that vitamin D(3)/RA treatment inhibits mycobacterial entry as well as survival within macrophages, possibly through rescue of phagosome maturation arrest. The developing knowledge in this area suggests that vitamin D(3)/RA may be of importance in the treatment of intracellular infection, particularly tuberculosis.
Anand
Paras K
PK
Molecular Biology Unit, Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
Kaul
Deepak
D
Sharma
Meera
M
D001665:Binding Sites; D045744:Cell Line, Tumor; D015536:Down-Regulation; D017930:Genes, Reporter; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000382:microbiology*; D050296:Microbial Viability / Q000187:drug effects; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D010587:Phagocytosis; D020218:Response Elements; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D014376:Tuberculosis / Q000276:immunology / Q000382:microbiology; D014807:Vitamin D / Q000378:metabolism* / Q000494:pharmacology
D008840:Microfilament Proteins; D014157:Transcription Factors; D014807:Vitamin D; C072061:coronin proteins; D014212:Tretinoin