title: Critical role of toll-like receptor 9 in morphine and Mycobacterium tuberculosis-Induced apoptosis in mice.
abstract: BACKGROUND
  Although it is established that opioid and Mycobacterium tuberculosis are both public health problems, the mechanisms by which they affect lung functions remain elusive.
  
  
  RESULTS
  We report here that mice subjected to chronic morphine administration and M. tuberculosis infection exhibited significant apoptosis in the lung in wild type mice as demonstrated by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay. Morphine and M. tuberculosis significantly induced the expression of Toll-like receptor 9 (TLR9), a key mediator of innate immunity and inflammation. Interestingly, deficiency in TLR9 significantly inhibited the morphine and M. tuberculosis induced apoptosis in the lung. In addition, chronic morphine treatment and M. tuberculosis infection enhanced the levels of cytokines (TNF-alpha, IL-1beta, and IL-6) in wild type mice, but not in TLR9 knockout (KO) mice. The bacterial load was much lower in TLR9 KO mice compared with that in wild type mice following morphine and M. tuberculosis treatment. Morphine alone did not alter the bacterial load in either wild type or TLR9 KO mice. Moreover, administration of morphine and M. tuberculosis decreased the levels of phosphorylation of Akt and GSK3beta in the wild type mice, but not in TLR9 KO mice, suggesting an involvement of Akt/GSK3beta in morphine and M. tuberculosis-mediated TLR9 signaling. Furthermore, administration of morphine and M. tuberculosis caused a dramatic decrease in Bcl-2 level but increase in Bax level in wild type mice, but not in TLR9 KO mice, indicating a role of Bcl-2 family in TLR9-mediated apoptosis in the lung following morphine and M. tuberculosis administration.
  
  
  CONCLUSIONS
  These data reveal a role for TLR9 in the immune response to opioids during M. tuberculosis infection.
authors.affiliation: Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States of America.
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.forename: Wanliang
authors.initials: W
authors.lastname: Shi
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Xiuli
authors.initials: X
authors.lastname: Sun
authors.forename: Xionglin
authors.initials: X
authors.lastname: Fan
authors.forename: Gene
authors.initials: G
authors.lastname: Lesage
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiumei
authors.initials: X
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Deling
authors.initials: D
authors.lastname: Yin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D016207:Cytokines / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D054884:Host-Pathogen Interactions; D020287:In Situ Nick-End Labeling; D008168:Lung / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009020:Morphine / Q000008:administration & dosage*; D009169:Mycobacterium tuberculosis / Q000502:physiology; D009294:Narcotics / Q000008:administration & dosage; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000382:microbiology / Q000503:physiopathology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D016207:Cytokines; D009294:Narcotics; D019253:Proto-Oncogene Proteins c-bcl-2; D051217:Toll-Like Receptor 9; D051028:bcl-2-Associated X Protein; D009020:Morphine; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3