Philipp Lachenmann: DELPHI Rationale


Schoeller Junkmann Prize 2002

Dr. Oliver Kassel

Institute of Genetics, Karlsruhe Research Center

Glucocorticoids inhibit MAP-kinase activity through increased expression and attenuation of proteasomal degradation of MKP-1

Glucocorticoids are well known for their anti-inflammatory, immune suppressive and anti-allergic actions. They function by binding to a receptor, the glucocorticoid receptor (GR) that resides in an inactive form in the cytoplasm of target cells. Upon interaction with the hormone, this receptor is transported into the nucleus where it binds to discreet nucleotide sequences to alter the expression of specific genes.

A rapid effect of the receptor has also been reported in negative regulation of action of transcription factors such as AP-1 or NF-kB. As these transcription factors control the expression of numerous pro-inflammatory genes, the inhibition of their activity by the GR has become a paradigm for the anti-inflammatory action of glucocorticoids. A completely different mechanism by which GR might exert its anti-inflammatory effects is the inhibition of signalling pathways that regulate inflammatory processes, in particular the extracellular regulated kinases (Erk)-1 and -2 pathways.

We have investigated the mechanism by which GR exerts this inhibition of Erk-1/2 in mast cells. This new mechanism involves a dual action of the GR. Glucocorticoids first increase the expression of MAP kinase phosphatase-1 (MKP-1) gene at the promoter level. This phosphatase is known to inactivate MAP kinases. MKP-1 induction is however not sufficient to inhibit Erk-1/2, since activation of mast cells rapidly targets MKP-1 for degradation by the proteasome. After a long time of treatment, glucocorticoids exert a second action by attenuating proteasomal degradation of MKP-1. Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation in mast cells. In NIH-3T3 fibroblasts, although glucocorticoids upregulate MKP-1 level, they do not attenuate the proteasomal degradation of this protein and consequently they are unable to inhibit Erk-1/2 activity.

These results identify MKP-1 as essential for glucocorticoid-mediated control of Erk-1/2 activation and unravel a novel regulatory mechanism for this anti-inflammatory drug. This mechanism may play an important role in the mediation of the anti-inflammatory action of glucocorticoids in mast cells.



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