Molecular and functional evidence for in vitro cytokine enhancement of human and murine target cell sensitivity to glucocorticoids:protection: TNF–a priming increases glucocorticoid inhibition of TNF–a –induced cytotoxicity/apoptosis

MONICA ALEJANDRA COSTAS; TRAPP, T.; PEREDA, M. P.; SAUER, J.; RUPPRECHT, R.; NAHMOD, V. E.; REUL J M; HOLSBOER, F.; ARZT, E.

J. Clin. Invest.

Año: 1996 vol. 98 p. 1409 - 1416

Cytokine-induced glucocorticoid secretion and glucocorticoid inhibition of cytokine synthesis and pleiotropic actions act as important safeguards in preventing cytokine overreaction. We found that TNF- a increased glucocorticoid-induced transcriptional activity of the glucocorticoid receptor (GR) via the glucocorticoid response elements (GRE) in L-929 mouse fibroblasts transfected with a glucocorticoid-inducible reporter plasmid. In addition, TNF- a also enhanced GR number. The TNF- a effect on transcriptional activity was absent in other cell lines that express TNF- a receptors but not GRs, and became manifest when a GR expression vector was cotransfected, indicating that TNF- a , independent of any effect it may have on GR number, has a stimulatory effect on the glucocorticoid-induced transcriptional activity of the GR. Moreover, TNF- a increased GR binding to GRE. As a functional biological correlate of this mechanism, priming of L-929 cells with a low (noncytotoxic) dose of TNF- a significantly increased the sensitivity to glucocorticoid inhibition of TNF- a –induced cytotoxicity/apoptosis. TNF- a and IL-1 b had the same stimulatory action on glucocorticoid- induced transcriptional activity of the GR via the GRE, in different types of cytokine/glucocorticoid target cells (glioma, pituitary, epithelioid). The phenomenon may therefore reflect a general molecular mechanism whereby cytokines modulate the transcriptional activity of the GR, thus potentiating the counterregulation by glucocorticoids at the level of their target cells. ( J. Clin. Invest. 1996. 98: 1409–1416.) Key words: cytokines • TNF- a • glucocorticoid receptor • glucocorticoid response element • apoptosis