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Role of enhanced glucocorticoid receptor sensitivity in inflammation in PTSD: insights from computational model for circadian-neuroendocrine-immune interactions.
Somvanshi, Pramod R; Mellon, Synthia H; Yehuda, Rachel; Flory, Janine D; Makotkine, Iouri; Bierer, Linda; Marmar, Charles; Jett, Marti; Doyle, Francis J.
Afiliación
  • Somvanshi PR; Harvard John Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts.
  • Mellon SH; Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Francisco, California.
  • Yehuda R; Department of Psychiatry, James J. Peters Veterans Affairs Medical Center, Bronx, New York.
  • Flory JD; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York.
  • Makotkine I; Department of Psychiatry, James J. Peters Veterans Affairs Medical Center, Bronx, New York.
  • Bierer L; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York.
  • Marmar C; Department of Psychiatry, James J. Peters Veterans Affairs Medical Center, Bronx, New York.
  • Jett M; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York.
  • Doyle FJ; Department of Psychiatry, James J. Peters Veterans Affairs Medical Center, Bronx, New York.
Am J Physiol Endocrinol Metab ; 319(1): E48-E66, 2020 07 01.
Article en En | MEDLINE | ID: mdl-32315214
Although glucocorticoid resistance contributes to increased inflammation, individuals with posttraumatic stress disorder (PTSD) exhibit increased glucocorticoid receptor (GR) sensitivity along with increased inflammation. It is not clear how inflammation coexists with a hyperresponsive hypothalamic-pituitary-adrenal (HPA) axis. To understand this better, we developed and analyzed an integrated mathematical model for the HPA axis and the immune system. We performed mathematical simulations for a dexamethasone (DEX) suppression test and IC50-dexamethasone for cytokine suppression by varying model parameters. The model analysis suggests that increasing the steepness of the dose-response curve for GR activity may reduce anti-inflammatory effects of GRs at the ambient glucocorticoid levels, thereby increasing proinflammatory response. The adaptive response of proinflammatory cytokine-mediated stimulatory effects on the HPA axis is reduced due to dominance of the GR-mediated negative feedback on the HPA axis. To verify these hypotheses, we analyzed the clinical data on neuroendocrine variables and cytokines obtained from war-zone veterans with and without PTSD. We observed significant group differences for cortisol and ACTH suppression tests, proinflammatory cytokines TNFα and IL6, high-sensitivity C-reactive protein, promoter methylation of GR gene, and IC50-DEX for lysozyme suppression. Causal inference modeling revealed significant associations between cortisol suppression and post-DEX cortisol decline, promoter methylation of human GR gene exon 1F (NR3C1-1F), IC50-DEX, and proinflammatory cytokines. We noted significant mediation effects of NR3C1-1F promoter methylation on inflammatory cytokines through changes in GR sensitivity. Our findings suggest that increased GR sensitivity may contribute to increased inflammation; therefore, interventions to restore GR sensitivity may normalize inflammation in PTSD.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Trastornos por Estrés Postraumático / Receptores de Glucocorticoides / Citocinas / Glucocorticoides Tipo de estudio: Diagnostic_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Adult / Humans / Male Idioma: En Revista: Am J Physiol Endocrinol Metab Asunto de la revista: ENDOCRINOLOGIA / FISIOLOGIA / METABOLISMO Año: 2020 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Trastornos por Estrés Postraumático / Receptores de Glucocorticoides / Citocinas / Glucocorticoides Tipo de estudio: Diagnostic_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Adult / Humans / Male Idioma: En Revista: Am J Physiol Endocrinol Metab Asunto de la revista: ENDOCRINOLOGIA / FISIOLOGIA / METABOLISMO Año: 2020 Tipo del documento: Article