Ligand‐induced differentiation of glucocorticoid receptor (GR) trans‐repression and transactivation: preferential targetting of NF‐κB and lack of I‐κB involvement

Q2 · MEDICINE

Article

Author: Ian M Adcock ; Peter J Barnes ; David A Stevens ; Yasuyuki Nasuhara

Glucocorticoids are highly effective in controlling chronic inflammatory diseases, such as asthma and rheumatoid arthritis, but the exact molecular mechanism of their anti‐inflammatory action remains uncertain. They act by binding to a cytosolic receptor (GR) resulting in activation or repression of gene expression. This may occur via direct binding of the GR to DNA (transactivation) or by inhibition of the activity of transcription factors such as AP‐1 and NF‐κB (transrepression).

The topically active steroids fluticasone propionate (EC50=1.8×10−11 M) and budesonide (EC50=5.0×10−11 M) were more potent in inhibiting GM‐CSF release from A549 cells than tipredane (EC50=8.3×10−10 M), butixicort (EC50=3.7×10−8 M) and dexamethasone (EC50=2.2×10−9 M). The anti‐glucocorticoid RU486 also inhibited GM‐CSF release in these cells (IC50=1.8×10−10 M).

The concentration‐dependent ability of fluticasone propionate (EC50=9.8×10−10 M), budesonide (EC50=1.1×10−9 M) and dexamethasone (EC50=3.6×10−8 M) to induce transcription of the β2‐receptor was found to correlate with GR DNA binding and occurred at 10–100 fold higher concentrations than the inhibition of GM‐CSF release. No induction of the endogenous inhibitors of NF‐κB, IκBα or I‐κBβ, was seen at 24 h and the ability of IL‐1β to degrade and subsequently induce IκBα was not altered by glucocorticoids.

The ability of fluticasone propionate (IC50=0.5×10−11 M), budesonide (IC50=2.7×10−11 M), dexamethasone (IC50=0.5×10−9 M) and RU486 (IC50=2.7×10−11 M) to inhibit a 3×κB was associated with inhibition of GM‐CSF release.

These data suggest that the anti‐inflammatory properties of a range of glucocorticoids relate to their ability to transrepress rather than transactivate genes.

British Journal of Pharmacology (1999) 127, 1003–1011; doi:10.1038/sj.bjp.0702613

01 Sep 1997·European Journal of PharmacologyQ3 · MEDICINE

Interleukin-2 and -4 induce resistance of granulocyte–macrophage colony-stimulating factor to corticosteroids

Q3 · MEDICINE

Article

Author: Ralph Brattsand ; Margareta Linden ; Susanne Larsson

In vitro pretreatment of human mononuclear blood cells with a combination of interleukin-2 and interleukin-4 decreases corticosteroid receptor affinity and reduces the anti-proliferative effects of corticosteroids. Similar abnormalities have been observed in mononuclear blood cells of steroid-resistant asthmatics. In vitro steroid resistance was induced by 48 h pretreatment of mononuclear blood cells from healthy individuals (n = 10) with interleukin-2 and interleukin-4 (500 Units (U)/ml). The effects of three structurally different corticosteroids (10(-7)-10(-11) M) on lipopolysaccharide-stimulated (10 ng/ml; 20 h) production of granulocyte-macrophage colony-stimulating factor (GM-CSF) were examined. GM-CSF production was efficiently inhibited by all three corticosteroids in the control cultures. Cortivazol was significantly more potent (IC50 = 3 x 10(-11) M) than budesonide and tipredane (IC50 = 2.5 x 10(-10) M and IC50 = 2 x 10(-10) M, respectively). However. interleukin-2 and interleukin-4 pretreatment counteracted the inhibitory effects of all three corticosteroids to a similar degree. The results highlight the importance of interleukin-2 and interleukin-4 in the induction of steroid resistance, since pretreatment of mononuclear blood cells with these cytokines impaired corticosteroid inhibition of GM-CSF production.

01 Jun 1997·Journal of Chromatography B: Biomedical Sciences and Applications

Determination of a major metabolite of tipredane in rat urine by high-performance liquid chromatography with column switching

Article

Author: D Wilkinson ; M.A.J Bayliss ; P.R Baker

An automated method, based on column-switching reversed-phase high-performance liquid chromatography, has been developed for the determination of a major metabolite of tipredane in rat urine. Samples are injected directly onto a cyanopropyl extraction column. The portion of eluate containing the metabolite is switched, via an injection loop, onto an octadecylsilane analytical column. The limit of quantification of the method was 25 ng/ml for a 20 microl injection volume of urine. The intra-assay precision (0.7-4.8%) and accuracy (94-105%), and the inter-assay precision (2.7-12.6%) and accuracy (94-105%), were acceptable. The analyte was found to be stable in rat urine when stored at room temperature for six days, in a freezer at or below -20 degrees C for twelve weeks, and when the samples were subjected to two freeze-thaw cycles. No significant interference was observed from tipredane and its major human metabolites, or urine constituents in male and female rats. The method was successfully used to analyse samples from a long-term toxicology study.

100 Deals associated with Tipredane

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	NDA/BLA	US	Bristol Myers Squibb Co.	-
Psoriasis	NDA/BLA	-	Bristol Myers Squibb Co.	-
Rhinitis, Allergic	NDA/BLA	US	Bristol Myers Squibb Co.	-
Skin Diseases	NDA/BLA	US	Bristol Myers Squibb Co.	-

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