Glucocorticoids downregulate gene expression of GM-CSF, NAP-1/IL-8, and IL-6, but not of M-CSF in human fibroblasts

Abstract

Cytokines such as granulocyte-macrophage colony-stimulating factor (GM- CSF), macrophage-CSF (M-CSF), neutrophil-activating peptide- 1/interleukin-8 (NAP-1/IL-8), and interleukin-6 (IL-6) are pivotal in the regulation of hematopoiesis and immune responses. In mesenchymal cells, their expression is induced by tumor necrosis factor alpha (TNF) and other agents. We now show that, while induction of cytokine expression by TNF in human lung fibroblasts was parallel, glucocorticoid hormones differentially affected their production. Dexamethasone (1 mumol/L) concordantly repressed expression of GM-CSF, NAP-1/IL-8 and IL-6. RNA and protein levels were reduced to approximately 5%, 20%, and 30% of control cells, respectively, as determined by Northern blot analyses and immunoassays. A 50% reduction of RNA levels for all three cytokines occurred in the range of 1 hour. In contrast, dexamethasone (1 mumol/L) did not decrease M-CSF RNA levels and protein release. M-CSF RNA and protein levels were maintained even when dexamethasone (1 mumol/L) was present for the whole duration of a 48-hour TNF stimulation. Further experiments showed that dexamethasone downregulates expression of GM-CSF, NAP-1/IL-8, and IL-6 mainly by decreasing the mRNA stability of these cytokines, and that the dexamethasone-mediated repression of cytokine expression depends on ongoing protein and RNA syntheses. Our study suggests that glucocorticoid hormones repress expression of a set of cytokine genes important in conditions of stress. However, they seem not to affect M- CSF expression, which is likely to be more crucial in maintaining long- term functions of myeloid cells.

NFAT‐regulated cytokine gene expression during tacrolimus therapy early after renal transplantation

“…activator protein-1 (AP-1) and nuclear factor kappa B (NF-kB)] that are required for the transcription of proinflammatory cytokines, including IL2, INFG and CSF2 [30,32]. Furthermore, glucocorticoids are reported to inhibit cytokine secretion by reducing mRNA stability [33], and by suppressing the cytokine-producing cell populations [34]. We observed that the two patients with ongoing rejection therapy with methylprednisolone (500-125 mg) presented significantly reduced E 0 , as well as strong inhibition of cytokines after dosing (RGE 1.5% and 11.1%).…”

Glycyrrhizin and related compounds down-regulate production of inflammatory chemokines IL-8 and eotaxin 1 in a human lung fibroblast cell line

“…Pulmonary fibroblasts have now been recognized as an active participant during inflammatory processes in the lung, playing a specialized role in the recruitment and regulation of immune cells that infiltrate the interstitial space. Through their regulatory mechanisms, lung fibroblasts generate many kinds of chemokines and cytokines, including IL-8, eotaxin 1, MCP-1, MIP-1a, RANTES, and GM-CSF, upon activation with inflammatory stimulants [1][2][3]. IL-8 (CXCL8) is one of the major chemokines with neutrophil chemotactic activity [4], and is produced by a variety of cells including lung fibroblasts activated with various stimulants [3][4][5][6][7][8].…”

Inflammatory vulnerability associated with the rh5‐HTTLPR genotype in juvenile rhesus monkeys

“…While this cellular demargination can also be a marker of bacterial infection, the latter is typically manifested by a large increase in total leukocyte count (Busch et al 1998;Nathan 2006). Apart from the effects on cell numbers, the release of glucocorticoids in response to acute stressors has also been associated with an inhibition of IL-6 responses to endotoxins (Ahmed & Ivashkiv 2000;Akira & Kishimot 1992;Tobler et al 1992;Waage et al 1990;Zitnik et al 1994). This inhibition of cellular reactions is distinct from the in vivo increase in IL-6 secretion from many nonlymphoid tissues, which has described as the proinflammatory bias seen after sustained psychological stress and sometimes in glucocorticoid resistance states, such as posttraumatic stress disorder (Kiecolt-Glaser et al 2003;Lutgendorf et al 1999;Maes et al 1998;Miller et al 2002).…”