11beta-hydroxysteroid dehydrogenases are regulated during the pulmonary granulomatous response to the mycobacterial glycolipid trehalose-6,6'-dimycolate.
OBJECTIVE
Tuberculosis has a staggering influence on world health, resulting in nearly 2 million deaths per year. The influence of glucocorticoids during Mycobacterium tuberculosis infection has been under investigation for decades; however, the identity of mycobacterial factors and the mechanism by which glucocorticoids are tissue specifically regulated to influence immune function during acute granuloma formation are unknown.


METHODS
One factor implicated in initiating immunopathology during M. tuberculosis infection is trehalose-6,6'-dimycolate (TDM), a glycolipid component of the mycobacterial cell wall. Intravenous administration of TDM causes inflammatory responses in lungs of mice similar to M. tuberculosis infection and has been used as a successful model to examine proinflammatory regulation and early events involved in the manifestation of pathology.


CONCLUSIONS
IL-6, IL-1alpha and TNF-alpha mRNA and protein peaked during the initiation of granuloma formation. Pulmonary corticosterone levels were elevated when the proinflammatory response was greatest, dropping to half of that upon the establishment of granuloma pathology on day 7. It is hypothesized that once corticosterone reaches the site of inflammation, the enzymes 11beta-hydroxysteroid dehydrogenases (11betaHSDs) can influence bioavailability by interconverting corticosterone and the inert metabolite 11-dehydrocorticosterone. RT-PCR demonstrated that pulmonary 11betaHSD type 1 mRNA decreased 4-fold and 11betaHSD type 2 (11betaHSD2) mRNA expression increased 2.5-fold on day 3 after injection, suggesting that corticosterone regulation in the lung, specifically the reduction of active corticosterone by 11betaHSD2, may influence the progression of granuloma formation in response to the mycobacterial glycolipid.
Abbott
A N
AN
University of Texas Medical School at Houston, Houston, TX 77030, USA.
Guidry
T V
TV
Welsh
K J
KJ
Thomas
A M
AM
Kling
M A
MA
Hunter
R L
RL
Actor
J K
JK
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003311:Cord Factors / Q000378:metabolism*; D003345:Corticosterone / Q000031:analogs & derivatives / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D015769:Granuloma, Respiratory Tract / Q000201:enzymology* / Q000382:microbiology* / Q000503:physiopathology; D007108:Immune Tolerance / Q000502:physiology; D008168:Lung / Q000201:enzymology / Q000382:microbiology / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014397:Tuberculosis, Pulmonary / Q000201:enzymology* / Q000382:microbiology* / Q000503:physiopathology; D015854:Up-Regulation / Q000502:physiology
D003311:Cord Factors; D016207:Cytokines; D012333:RNA, Messenger; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C003552:11-dehydrocorticosterone; D003345:Corticosterone