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Published ahead of print on November 7, 2007, doi:10.1165/rcmb.2007-0079OC

Am. J. Respir. Cell Mol. Biol., Volume 38, Number 4, April 2008, 414-422

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Submitted on March 8, 2007
Revised on October 24, 2007

Cell Density and Serum Exposure Modify the Function of the Glucocorticoid Receptor C/EBP Complex

Jing-Qing Yang1, Jochen J Rudiger1, J Margaret Hughes2, Stephanie Goulet1, Mesut M Gencay-Cornelson1, Pieter Borger1, Michael Tamm1, and Michael Roth3*

1 Department of Pneumology, Pulmonary Cell Research, University Hospital Basel, Basel, Switzerland, 2 University of Sydney, Faculty of Pharmacy, Camperdown, NSW, Australia, 3 Department of Pneumology, Pulmonary Cell Research, University Hospital Basel, Basel, Switzerland; Department of Molecular Medicine, The Woolcock Institute for Medical Research, Camperdown, NSW, Australia

* To whom correspondence should be addressed. E-mail: Rothmic{at}uhbs.ch.

The glucocorticoid receptor is a major control factor for proliferation, differentiation and inflammation. Our knowledge about the glucocorticoid receptor is focused on its function as a transcription regulator. However, cells do not always respond to steroids in the same way or develop resistance. The mechanism underlying such a modified steroid response is not well understood and may depend on the microenvironment of the cells or on the stage of their differentiation. Therefore we studied the effect of cell density and inflammatory conditions on the expression, compartmentalisation, activation, and the anti-proliferative function of the glucocorticoid receptor in primary human lung fibroblast cultures. In sub-confluent cells the glucocorticoid receptor was located peri-nuclear, while in confluent cells it was ubiquitously expressed. Serum stimulation up-regulated the level of glucocorticoid receptor mRNA and protein under all conditions. In sub-confluent cells dexamethasone activated the nuclear accumulation and DNA binding of the glucocorticoid receptor persistently, while in confluent cells its activity declined after 6 hours. In sub-confluent cells, but not in confluent cells, the glucocorticoid receptor interacted with a 42 kDa, but not the 30 kDa C/EBP-{alpha} isoprotein, which resulted in an up-regulation of p21(Waf1/Cip1) expression and suppression of proliferation. In confluent cells glucocorticoids induced p27(Kip1) expression via p38 MAP kinase and a 52 kDa C/EBP-{beta} isoprotein. However, p27(Kip1) did not mediate the anti-proliferative effect of glucocorticoids, but simultaneous inhibition of p21(Waf1/Cip1)and p27(Kip1) unlocked contact inhibition in confluent cells. Our results indicate that cell density and serum exposure alter the localisation and function of the glucocorticoid receptor.






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