Differential expression of genes regulated by the glucocorticoid receptor pathway in patients with pulmonary tuberculosis

GALLUCCI G; DIAZ A; FERNANDEZ R; BONGIOVANNI B; IMHOFF M; MASSA E; SANTUCCI N; BERTOLA D; LIOI S; BAY ML; BOTTASSO O; D´ATTILIO L

LIFE SCIENCES

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2022 vol. 301 p. 1 - 10

0024-3205

Aims and Main methods:Tuberculosis (TB) remains one of the leading causes of death worldwide. Previous studies in TB patients showed an immuno-endocrine imbalance characterized by a disease-severity associated increase in plasma levels of proinflammatory cytokines and glucocorticoids (GCs).To analyze the potential immunomodulatory effect of circulating GCs over peripheral blood mononuclear cells (PBMC) from TB patients, we investigated the expression of positively (anti-inflammatory-related genes ANXA1; FKBP51; GILZ, NFKBIA, and NFKBIB) and negatively (inflammatory genes: IL-6, IL-1β, and IFN-γ) Glucocorticoids Receptors (GR)-regulated genes by RT-qPCR, together with specific lymphoproliferation. To appraise the immunoendocrine environment of these cells, plasma concentrations of cytokines and hormones, together with specific lymphoproliferation were also assessed.Materials and Methods:Gene expression was quantified by RT-qPCR, specific lymphoproliferation by 3H-thymidine incorporation, whereas plasma cytokines and hormones levels by ELISAwere quantified by ELISA. Key findings:Transcripts of ANXA1, GILZ, NFKBIB, and NFKBIA appeared significantly increased in patients, whereas FKBP51, IL-6, IL-1β, and NF-κB remained unchanged. Upon analyzing according to disease severity, mRNA levels for ANXA1 and NFKBIB were even higher in moderate and severe patients. GILZ was increased in moderate cases, with NFKBIA and IL-1 β being higher in severe ones, who also displayed increased GRβ transcripts. TB patients had reduced plasma DHEA concentrations together with increased pro and anti-inflammatory cytokines (IFN-γ, IL-6, and IL-10) cortisol and cortisol/DHEA ratio, more evident in progressive cases, in whom their PBMC also showed a decreased mycobacterial-driven proliferation. The cortisol/DHEA ratio and GRα expression were positively correlated with GR-regulated genes mainly in moderate patients. Significance:The increased expression of cortisol-regulated anti-inflammatory genes in TB patients-PBMC, predominantly in progressive disease, seems compatible with a relatively insufficient attempt to downregulate the accompanying inflammation.