The effects of androstenediol and dehydroepiandrosterone on the course and cytokine profile of tuberculosis in BALB/c mice.
Immunity to Mycobacterium tuberculosis requires a T helper 1 (Th1) cytokine balance accompanied by tumour necrosis factor-alpha (TNF-alpha), and activated macrophages. These facets of the immune response are sensitive to suppression by glucocorticoids (GC), which can reactivate and exacerbate tuberculosis in man and animals. Dehydroepiandrosterone (DHEA) and its derivative, 3beta,17beta androstenediol (AED), are reported to have antiglucocorticoid properties in vivo. We therefore investigated the effects of predetermined optimal doses of these compounds, on the course of pulmonary tuberculosis in an established model in BALB/c mice in which an early phase of Th1-mediated response accompanied by adrenal hyperplasia, is followed by a switch to Th2, progressive loss of TNF-alpha expression and disease progression. Both compounds were protective, particularly AED which caused a fall in bacterial counts and prolonged survival. These effects correlated with the appearance within 3 days of cellular infiltrates rich in cells expressing interleukin-2 (IL-2), IL-1alpha and TNF-alpha, and with partial suppression of the switch to IL-4 producing cells that occurred in controls. AED also caused enhanced development of granulomas at 14 days, and persistence of granuloma formation to 120 days, with a corresponding suppression of areas affected by pneumonia. Much of the therapeutic effect of AED and DHEA was obtained by treating for only the first 3 weeks, which is the phase of adrenal hyperplasia. These results suggest that the ratio of GC to anti-GC steroids may play a role in the pathogenesis of tuberculosis, and further investigation could lead to novel treatment strategies.
Hernandez-Pando
R
R
Experimental Pathology Laboratory, Department of Pathology, Instituto Nacional de la Nutricion 'Salvador Zubiran', Mexico City, Mexico.
De La Luz Streber
M
M
Orozco
H
H
Arriaga
K
K
Pavon
L
L
Al-Nakhli
S A
SA
Rook
G A
GA
D015114:Androstenediol / Q000627:therapeutic use*; D000818:Animals; D015169:Colony Count, Microbial; D016207:Cytokines / Q000032:analysis / Q000378:metabolism*; D003687:Dehydroepiandrosterone / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000032:analysis / Q000378:metabolism; D007376:Interleukin-2 / Q000032:analysis / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D013997:Time Factors; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism
D016207:Cytokines; D007375:Interleukin-1; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D003687:Dehydroepiandrosterone; D015114:Androstenediol