title: Pathogenetic role, in human and murine tuberculosis, of changes in the peripheral metabolism of glucocorticoids and antiglucocorticoids.
abstract: Immunity to tuberculosis (TB) requires a Th1 pattern of cytokine release, dominated by interleukin-2 (IL-2) and interferon gamma (IFN gamma). In experimental models even a minor Th2 component (characterized by production of IL-4) abrogates immunity, and leads to an immunopathology that mimics the human disease. Increased exposure of T cells to glucocorticoids drives them towards a Th2 cytokine profile and could therefore help to explain the presence of an inappropriate Th2 component in TB. Analysis of adrenal steroid metabolites in 24-h urine collections revealed a striking increase in metabolites of active cortisol relative to metabolites of inactive cortisone. This indicates a change in the balance of 11 beta-hydroxysteroid dehydrogenase to 11 beta-ketosteroid reductase. The site of this disease-associated alteration in reductase/dehydrogenase balance may be the lung. The lung contains 11 beta HSD-1, (a reversible oxido-reductase) which in the liver works as a reductase. In the normal lung it functions paradoxically as a reductase, but it can alter its function in the presence of cytokines. TB patients (like other ill individuals) also show reduced 24-h urinary secretion of dehydroepiandrosterone (DHEA) derivatives. Since these have antiglucocorticoid functions in vivo, this fall may exacerbate the effects of the reduced inactivation of cortisol and loss of diurnal rhythm, and contribute to immunological dysfunction. Recent studies of TB in mice, and in children during infancy, adrenarche and puberty, suggest that the ratio of cortisol to DHEA may be crucial both to susceptibility and to the pathology of the disease that develops.
authors.affiliation: Department of Bacteriology, UCL Medical School, London, UK. g.rook@ucl.ac.uk
authors.forename: G A
authors.initials: GA
authors.lastname: Rook
authors.forename: R
authors.initials: R
authors.lastname: Hernandez-Pando
mesh_terms: D000818:Animals; D003687:Dehydroepiandrosterone / Q000378:metabolism / Q000652:urine; D005938:Glucocorticoids / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000652:urine; D006727:Hormone Antagonists / Q000627:therapeutic use*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism / Q000652:urine; D008168:Lung / Q000378:metabolism; D051379:Mice; D014397:Tuberculosis, Pulmonary / Q000378:metabolism* / Q000652:urine
chemical_list: D005938:Glucocorticoids; D006727:Hormone Antagonists; D003687:Dehydroepiandrosterone; D006854:Hydrocortisone