Molecular and functional evidence for in vitro cytokine enhancement of human and murine target cell sensitivity to glucocorticoids. TNF-alpha priming increases glucocorticoid inhibition of TNF-alpha-induced cytotoxicity/apoptosis.

Abstract

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-␣ 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-␣ also enhanced GR number. The TNF-␣ effect on transcriptional activity was absent in other cell lines that express TNF-␣ receptors but not GRs, and became manifest when a GR expression vector was cotransfected, indicating that TNF-␣ , 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-␣ increased GR binding to

Glucocorticoid receptor down-Regulates c-jun amino terminal kinases induced by tumor necrosis factor ? in fetal rat hepatocyte primary cultures

“…54 In agreement with these data, it has been reported that treatment of A549 cells with TNF-␣ targeted GR, possibly by phosphorylation, to remain in cytoplasm. 55 However, TNF-␣ increased the GR number and glucocorticoidinduced transcriptional activity of the GR in L-929 mouse fibroblast, 56 which is in contradiction with the above data. These divergences can reflect different genetic cell programs, because TNF-␣ is toxic in L-929 cells.…”

TNF-α enhances estrogen-induced cell proliferation of estrogen-dependent breast tumor cells through a complex containing nuclear factor-kappa B

“…TNF-a was initially identified as a protein capable of inducing necrosis in mouse solid tumors (Larrick and Wright, 1990) and apoptosis in several different cell lines (Beg and Baltimore, 1996;Costas et al, 1996Costas et al, , 2000Liu et al, 1996;Wang et al, 1998;Franco et al, 2002). Herein, we demonstrated that this inflammatory cytokine does not induce breast ductal tumor cell apoptosis, even in the presence of the NF-kB inhibitor SZ, in a dose that significantly inhibits this transcription factor binding to its specific DNA sequence.…”

“…Nevertheless, it has been demonstrated that several cell lines are not sensitive to the proapoptotic signal unless the novo synthesis of antiapoptotic NF-kB target genes is blocked (Beg and Baltimore, 1996;Costas et al, 1996Costas et al, , 2000Liu et al, 1996;Wang et al, 1998;Franco et al, 2002).…”

“…Although this cytokine was initially identified as a macrophage-derived serum protein that induces necrosis in mouse solid tumors in mice (Larrick and Wright, 1990), only a few cell types are naturally sensitive to its proapoptotic activity. In fact, most cells require the TNF-a activation of the NF-kB protective pathway to be blocked before apoptosis can occur (Beg and Baltimore, 1996;Costas et al, 1996Costas et al, , 2000Liu et al, 1996;Wang et al, 1998;Franco et al, 2002).…”

Somatostatin Increases Glucocorticoid Binding and Signaling in Macrophages by Blocking the Calpain-specific Cleavage of Hsp 90

“…This concept is supported by findings of a direct correlation between the concentration of GR in a target cell and the sensitivity of this cell to glucocorticoids (10). In addition, the cell concentration of GR has been already shown to be modulated by a number of mediators including glucocorticoids, cAMP-inducing agonists, and cytokines such as TNF-␣ and interleukin-2, -4, and -13 (11)(12)(13)(14)(15). We found that somatostatin increases glucocorticoid binding and signaling in RAW 264.7 macrophages.…”