Functional cross-talk among cytokines, T-cell receptor and glucocorticoid receptor transcriptional activity and action

E. ARZT; D.KOVALOVSKY; L.M. IGAZ; M.COSTAS; P.PLAZAS; D.REFOJO; M.P.PEREDA; J.M.H.M.REUL; G.STALLA; F.HOLBOER

ANNALS OF THE NEW YORK ACADEMY OF SCIENCES.

Año: 2000 vol. 917 p. 672 - 677

0077-8923

The main communicators between the neuroendocrine and immune systems are cytoquines and hormones. We studied the molecular interaction between immune activators (cytoquines and T-cell receptors) and the glucocorticoid receptor (GR) in cells in wich glucocorticoids play a key regulatory function: (1) cellular targets of TNF-induced cytotoxicity; (2) the pituitary gland; and (3) thymic cells. Cytoquines (TNF-alpha and IL-1) increase glucocorticoid-induced transcriptional activity of the GR via tha DNA-glucocorticoid response elements (GRE) in cells transfected with a glucocorticoid-inducible reporter plasmid. As a functional physiological correlate, priming of fibroblastic cells with a low dose of TNF significantly increases the sensitivity to glucocorticoid inhibition of TNF-induced apoptosis (without involving NF-kB). Priming of AtT-20 mouse corticotrophs and Cushing pituitary cells with IL-1 increases the sensitivity to glucocorticoid inhibition of CRH-induced ACTH/POMC expression. In tymocytes, activation of the T-cell receptor counteracts the glucocorticoid- induced tymic apoptosis by downregulating the glucocorticoid action on gRE-driven apoptotic genes. Thus, cytokines and immune mediators prevent their own deleterious effects notonly by stimulating glucocorticoid production, but also modifying the sensitivity of the target cells for the glucocorticoid counterregulatory action.The functional cross-talk at the molecular level between immune signals and glucocorticoids is essential to determine the biological response to both mediators and constitutes the ultimate level of interaction between the immune and neuroendocrine mediators.