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Development of a new generation of anti-inflammatory steroids based on novel type of molecular crosstalk between the glucocorticoid receptor and NF-KAPPAB transcription factors

Objective

The recent discovery of molecular crosstalk between the glucocorticoid receptor and members of the Rel family of transcription factors provides a basis.
- to obtain a better understanding of the anti-inflammatory and immuno-suppressive action of glucocorticoids.
-to develop cellular test systems to determine efficiently the anti-inflammatory and immuno-suppresive action of existing steroids and other agents.
- to provide a basis for the development of new steroids and other drugs in this area.

Synthetic glucocorticoids are hormone analogs with strong anti-inflammatory and immuno-suppressive properties and are therefore widely used as drugs in asthma, rheumatoid arthritis, topic dermatitis, and after organ transplantation. Despite the fact that these substances closely resemble the normal hormone present in the body, side effects are very common and therefore can cause serious problems (e.g. osteoporosis in chronically treated patients). A second important problem preventing patients from receiving adequate treatment with glucocorticoids is pre-existing or developing resistance to steroid treatment. Like other steroids, glucocorticoids mediate their effects upon binding to high-affinity receptor proteins acting in the nucleus of the cell as ligand-activatable transcription factors switching on (or off) specific target genes. Steroids and their cognate receptors however are not the only type of signal molecules involved in expediating extracellular signals into the nucleus governing gene transcription; a (probably) limited number of other relatively well-known signalling pathways are present in a given cell, usually activated by factors of polypeptide nature (cytokines, peptide hormones and growth factors) as they bind to specific receptors in the plasma membrane.

Signal transduction along these pathways also results in changes in gene expression and it is generally supposed that e.g. over-stimulation by cytokines is causative in the diseased state of the inflammatory manifestation. An important signal transduction pathway, which is over-activated in hyper responsive situation, utilizes members of the Rel transcription factor family, among which NF-KB. Interestingly the concept has begun to emerge recently that steroids can affect some of these other signal transduction pathways at the level of nuclear transcription by (mutual) interference (crosstalk) with the transcription factors employed by these other signalling circuits. In collaboration between the Netherlands Institute for Developmental Biology (Hubrecht Laboratory) and the Karolinska Institute, Department of Medical Nutrition (prof. J.-A.Gustafsson) it was discovered that the immunosuppressive activity of glucocorticoids can possibly be explained by the fact that upon exposure to the hormone the glucocorticoid receptor can neutralize certain specific Rel family members by direct protein-protein binding and thus preventing activation of transcription of genes normally mediated by these factors.

Moreover it was observed that the phenomenon of trans-repression is effective in both ways as RelA is also able to repress gene activation by glucocorticoids through their cognate receptor. These findings provide a basis for a general mechanism explaining the immunosuppressive action of glucocorticoids and offer the possibility to exploit these new ideas in developing effective test systems. In these cellular reporter systems the repressive activity of synthetic glucocorticoids can be tested in comparison to their (classical) capacity to activate and upregulate glucocorticoid-specific target genes. This approach will offer the participants in this proposed research project to test existing and newly developed synthetic glucocorticoids for both repressive and activating properties. Moreover it is considered to be essential within the scope of this project to verify findings in these test systems in primary human material in vitro. It can be expected that this will lead to new glucocorticoid analogs, which are still strongly immunosuppressive, but have less side effects. Keywords: inflammation; asthma; steroids; glucocorticoids; transcription factor molecular cross talk.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

NETHERLANDS INSTITUTE FOR DEVELOPMENTAL BIOLOGY
Address
8,Uppsalalaan 8
3584 CT Utrecht
Netherlands

Participants (3)

GERMAN CANCER RESEARCH CENTER
Germany
Address
Im Neuenheimer Feld 280
69120 Heidelberg
IMPERIAL COLLEGE OF SCIENCE, TECHNOLOGY AND MEDICINE
United Kingdom
Address
Dovehouse Street
London
KAROLINSKA INSTITUTE
Sweden
Address
Novum Huddinge Sjukhus
141 86 Huddinge