Anti-inflammatory Action Of Dexamethasone Research Articles

Involvement of proton-sensing receptor TDAG8 in the anti-inflammatory actions of dexamethasone in peritoneal macrophages

Dexamethasone (DEX), a potent glucocorticoid, increased the expression of T-cell death associated gene 8 (TDAG8), a proton-sensing G protein-coupled receptor, which is associated with the enhancement of acidic pH-induced cAMP accumulation, in peritoneal macrophages. We explored the role of increased TDAG8 expression in the anti-inflammatory actions of DEX. The treatment of macrophages with either DEX or acidic pH induced the cell death of macrophages; however, the cell death was not affected by TDAG8 deficiency. While DEX inhibited lipopolysaccharide-induced production of tumor necrosis factor-α, an inflammatory cytokine, which was independent of TDAG8, at neutral pH, the glucocorticoid enhanced the acidic pH-induced inhibition of tumor necrosis factor-α production in a manner dependent on TDAG8. In conclusion, the DEX-induced increase in TDAG8 expression is in part involved in the glucocorticoid-induced anti-inflammatory actions through the inhibition of inflammatory cytokine production under the acidic pH environment. On the other hand, the role of TDAG8 in the DEX-induced cell death is questionable.

Wogonin Prevents Immunosuppressive Action but Not Anti‐Inflammatory Effect Induced by Glucocorticoid

Glucocorticoid, such as dexamethasone, has anti-inflammatory and immunosuppressive action as major pharmacological effects. The latter action caused by lymphocyte apoptosis is not only a therapeutic effect but also an adverse reaction. Wogonin, a plant flavone found in Scutellaria baicalensis Georgi, inhibited dexamethasone-induced apoptotic changes, such as DNA fragmentation, nuclear condensation, phosphatidylserine translocation, and caspase activation in rat thymocytes. Since wogonin inhibited dexamethasone-induced DNA fragmentation in a noncompetitive manner, a target of this flavone is unlikely to be an antagonist of glucocorticoid receptor. Wogonin did not only act as an inhibitor of caspases, but also protected apoptosis induced by other glucocorticoids. Since wogonin reduced one of the major pharmacological effects of dexamethasone, we examined whether this flavone diminishes the anti-inflammatory action, another pharmacological effect. The anti-inflammatory action of dexamethasone was evaluated by carrageenan-induced paw edema model. Although dexamethasone significantly suppressed paw edema induced by carrageenan, wogonin had no effect on the anti-inflammatory action of dexamethasone. These results suggest that wogonin may be a useful compound to reduce the immunosuppressive side effect of glucocorticoid.

Dexamethasone Inhibits Tumor Necrosis Factor-α-Induced Expression of Macrophage Inflammatory Protein-2 and Adhesion of Neutrophils to Endothelial Cells

Macrophage inflammatory protein-2 (MIP-2) belongs to the C-X-C subfamily of chemokines and appears to play an important role in cytokine-induced inflammatory and immune cell-mediated responses. We found that tumor necrosis factor-α (TNF-α) time- and dose-dependently increased gene and protein expression of MIP-2 in endothelial cells. Moreover, it was observed that dexamethasone treatment inhibited endothelial cell expression of MIP-2 in response to TNF-α stimulation and markedly reduced the number of adherent neutrophils. Moreover, we found that a monoclonal antibody against murine MIP-2 abolished neutrophil adhesion to TNF-α-activated endothelial cells. These data demonstrate that TNF-α induces expression of MIP-2 in endothelial cells and support the hypothesis that the anti-inflammatory action of dexamethasone may, at least in part, be attributable to an inhibition of MIP-2 induction on cytokine-activated endothelial cells.

Inhibition by dexamethasone of the lipopolysaccharide-induced increase in IL-6 mrna abundance and IL-6 production in human polymorphonuclear leukocytes

Interleukin-6 (IL-6) is a key inflammatory cytokine that is produced by various cell types including polymorphonuclear leukocytes (PMNs). However, the pathophysiological roles of IL-6 produced by human PMNs are unclear. Bacterial lipopolysaccharide (LPS) induced marked increase in IL-6 production, determined by enzyme-linked immunosorbent assay, and IL-6 mRNA abundance determined by reverse transcription-polymerase chain reaction analysis, in purified human PMNs. Both effects of LPS were inhibited in a dose-dependent manner by dexamethasone (10 −6 to 10 −8M). IL-6 receptor mRNA was constitutively present in PMNs and its abundance was not affected by either LPS or dexamethasone. These results indicate that PMNs are an important source of IL-6 in acute inflammatory reactions, and that the anti-inflammatory actions of dexamethasone is attributable in part to inhibition of IL-6 production by these cells. The constitutive presence of IL-6 receptor mRNA in PMNs suggests that IL-6 may exert pathophysiological effects on these cells.

Study on IL-8 Expression in Peripheral Blood Monocytes

Background: Peripheral blood monocytes are important immune effector cells that play a fundamental role in cellular immunity. In addition to their antigen-presenting and phagocytic activities, monocytes/macrophage produce a vast array of regulatory and chemotactic cytokines. Interleukin-8(IL-8), a potent neutrophil-activating and chemotactic peptide, is produced in large quantities by mononuclear phagocytes and may be an important mediator of local and systemic inflammation. Overexpression by IL-8 of such inflammation may be an important step of tissue injury frequently seen in inflammatory reaction. So it could be hypothesized that the agents which block the production of IL-8 can decrease the inflammatory reaction and tissue injury. To evaluate this, we described the effect of Dexamethasone, , Indomethacin and Interferon-(IFN-) on IL-8 mRNA and protein expression from LPS-stimulated human peripheral blood monocytes(PBMC). Method: PBMC was isolated from healthy volunteers. To evaluate the effect of Dexamethasone, & Indomethacin, these drug were treated for 1 hour before and after LPS stimulation and IFN- was only treated I hour before the LPS stimulation. Northern blot analysis for IL-8 mRNA and ELISA for immunoreactive IL-8 protein in culture supernatant were performed. We repeated above experiment three times for Northern blot analysis and two times for ELISA and got the same result. Results: 1) Pre- and post-treatment of Dexamethasone suppressed both the LPS stimulated IL-8 mRNA expression and IL-8 protein release in PBMC. 2) IFN- pre-treatment suppressed the IL-8 mRNA expression and IL-8 protein release in unstimulated cells. 3) In LPS stimulated cells, IFN- suppressed the IL-8 mRNA expression but IL-8 protein release suppression was not observed. 4) and Indomethacin exert no effect on the LPS-stimulated IL-8 mRNA and protein expression in concentration used in this experiment (, Indomethacin; ). Conclusion: One of the mechanism of antiinflammatory action of Dexamethasone can be explained by the suppressing effect of IL-8 production in some extent and by this antiinflammatory effect, dexamethasone can be used to suppress local and systemic inflammation mediated by IL-8.

Effect of dexamethasone on neutrophil accumulation and oedema formation in rabbit skin: an investigation of site of action.

1. The anti-inflammatory actions of dexamethasone on vascular and leukocyte responses in rabbit skin were investigated. 2. Neutrophil accumulation and oedema formation were simultaneously measured as the local accumulation of i.v. administered 111In-labelled neutrophils and 125I-labelled albumin. Systemically administered dexamethasone (3 mg kg-1) inhibited neutrophil accumulation induced by i.d. zymosan activated plasma (ZAP), N-formyl-methionyl-leucyl-phenylalanine (FMLP) and leukotriene B4 (LTB4) when co-injected with prostaglandin E2 (PGE2). Dexamethasone also inhibited oedema formation elicited by these stimuli and the responses induced by i.d. platelet activating factor (PAF)+PGE2 and bradykinin (BK)+PGE2. 3. Intradermal dexamethasone (2 x 10(-10) mol per site) but not indomethacin (10(-8) mol per site) inhibited oedema formation induced by i.d. ZAP+PGE2 and BK+PGE2. This inhibitory effect of dexamethasone was significant only with pretreatment periods of 4 h, shorter pretreatment periods resulting in greatly reduced effects. Intradermal dexamethasone had no effect on neutrophil accumulation induced by ZAP+PGE2. 4. Intradermal dexamethasone (2 x 10(-10) mol per site) had no effect on increase in blood flow induced by PGE2 as measured by 133Xenon clearance. 5. The accumulation of neutrophils isolated from donor rabbits pretreated with i.v. saline or dexamethasone (3 mg kg-1) was investigated in untreated recipient rabbits. The accumulation of neutrophils, induced by ZAP+PGE2, FMLP+PGE2 and LTB4+PGE2, from dexamethasone-pretreated donors was significantly smaller than the accumulation of neutrophils from saline-pretreated donors. 6. The results of this study suggest that dexamethasone can have a direct effect on vascular endothelial cells resulting in an inhibition of oedema formation. 7. Neutrophil accumulation can be inhibited by an effect of dexamethasone on the neutrophil itself or on the vascular endothelium. These results indicate that at least part of the inhibitory effect is on the circulating neutrophil induced by dexamethasone or a dexamethasone-induced product.

Action of dexamethasone in an equine model of acute non-immune inflammation

In a crossover study in seven New Forest ponies the actions of dexamethasone, at a dose rate of 0.06 mg kg-1 administered intravenously, were compared with those of a placebo treatment. Dexamethasone exerted expected effects on plasma and inflammatory exudate concentrations of cortisol and on blood glucose concentration and circulating leucocyte numbers, but it failed to affect exudate concentrations of the eicosanoids, prostaglandin E2, thromboxane B2, 6-keto-PGF1 alpha and leukotriene B4. These findings do not support the hypothesis that the anti-inflammatory actions of dexamethasone in the horse are mediated by inhibition of phospholipase A2.

Problems and results in testing the possible general mode of action of glucocorticoids in rat adjuvant arthritis.

The antiinflammatory action of dexamethasone in both phases of rat adjuvant arthritis was significantly reduced by injection of the RNA synthesis inhibitor actinomycin D into the inflamed paw. This effect is apparently caused by inhibition of RNA/protein synthesis and not by actinomycin D irritant activity. Thus, the present data support the view of indirect glucocorticoid activity via gene expression also in subacute and chronic adjuvant arthritis. The dexamethasone-induced antiinflammatory protein seems to be synthetized at the site of inflammation.

The role of glucocorticoid receptor and gene expression in the anti-inflammatory action of dexamethasone.

GLUCOCORTICOIDS are potent anti-inflammatory agents, but the molecular mechanisms involved in this activity are not yet understood. The biological actions of various steroid hormones have been shown to be mediated by functional proteins synthesised following translocation of a hormone-cytoplasmic receptor complex into the nucleus1,2. It is still not clear, however, whether the anti-inflammatory effects of glucocorticoids are mediate via binding to a cytoplasmic receptor in target cells and subsequent activation of gene expression3, although glucocorticoid receptors have been demonstrated in HTC cells, liver5, thymocytes6 and lymphocytes7. The results reported here suggest that a glucocorticoid receptor and the induction of gene expression are involved in the anti-inflammatory action of dexamethasone.