Transrepression Function of the Glucocorticoid Receptor Regulates Eyelid Development and Keratinocyte Proliferation but Is Not Sufficient to Prevent Skin Chronic Inflammation

Abstract

Glucocorticoids (GCs) play a key role in skin homeostasis and stress responses acting through the GC receptor (GR), which modulates gene expression by DNA binding-dependent (transactivation) and -independent (transrepression) mechanisms. To delineate which mechanisms underlie the beneficial and adverse effects mediated by GR in epidermis and other epithelia, we have generated transgenic mice that express a mutant GR (P493R, A494S), which is defective for transactivation but retains transrepression activity, under control of the keratin 5 promoter (K5-GR-TR mice). K5-GR-TR embryos exhibited eyelid opening at birth and corneal defects that resulted in corneal opacity in the adulthood. Transgenic embryos developed normal skin, although epidermal atrophy and focal alopecia was detected in adult mice. GR-mediated transrepression was sufficient to inhibit keratinocyte proliferation induced by acute and chronic phorbol 12-myristate 13-acetate exposure, as demonstrated by morphometric analyses, bromodeoxyuridine incorporation, and repression of keratin 6, a marker of hyperproliferative epidermis. These antiproliferative effects were mediated through negative interference of GR with MAPK/activator protein-1 and nuclear factor-kappaB activities, although these interactions occurred with different kinetics. However, phorbol 12-myristate 13-acetate-induced inflammation was only partially inhibited by GR-TR, which efficiently repressed IL-1beta and MMP-3 genes while weakly repressing IL-6 and TNF-alpha. Our data highlight the relevance of deciphering the mechanisms underlying GR actions on epithelial morphogenesis as well as for its therapeutic use to identify more restricted targets of GC administration.

Glucocorticoid receptor antagonizes EGFR function to regulate eyelid development

“…Our previous studies reported an EOB phenotype in K5-GR and K5-GR-TR embryos that was indeed the most consistent epithelial defect found in both transgenic mouse models Donet et al, 2008). In addition, our data demonstrated that the transrepression function of the GR is sufficient to cause these epithelial anomalies (Donet et al, 2008).…”

“…In addition, our data demonstrated that the transrepression function of the GR is sufficient to cause these epithelial anomalies (Donet et al, 2008). It was indeed surprising to find open eyelids in GR gain-and lossof-function mouse models although, undoubtedly, it further supports a key role for this transcription factor in ocular epithelial morphogenesis.…”

“…In addition, we have shown that transgenic mice with keratinocytetargeted overexpression of GR (K5-GR mice) featured numerous epithelial defects including epidermal defects and an eyelid opening at birth phenotype (EOB). Overexpression of GR transrepression function in keratinocytes (K5-GR-TR mice) also elicited epithelial alterations that partially overlapped with those found in K5-GR mice (Cascallana et al, 2005;Donet et al, 2008). Remarkably, K5-GR-TR mice featured an EOB phenotype identical to K5-GR mice, indicating that the transrepression function of the GR is sufficient to cause these epithelial ocular anomalies (Donet et al, 2008).…”

“…In fact, knock-out GR -/-mice die perinatally whereas mice carrying a point mutation which abrogates the dimerization-dependent DNA binding of GR (GR dim/dim ) are viable (Cole et al, 1995;Reichardt et al, 1998). This distinction, however, is not so clear-cut since GR monomers are also able to bind certain gene promoters and thus, regulate gene transcription (Adams et al, 2003;Rogatsky et al, 2003): In the last years, we have demonstrated that GR is a key player in epithelial development by analyzing genetically modified mouse models of GR gain-and loss-of-function (Pérez et al, 2001;Cascallana et al, 2003;Cascallana et al, 2005;Donet et al, 2008;Bayo et al, 2008). We have recently reported that only the epidermis of GR -/-but not GR dim/dim embryos shows major defects, suggesting that dimerization dependent DNA binding by GR is dispensible for epidermal development .…”

Glucocorticoids and circadian clock control of cell proliferation: At the interface between three dynamic systems

“…This indicates that the GR participates in the decision between proliferation and differentiation in a cell autonomous manner [130]. In contrast to what was seen in the case of stress erythropoiesis, this role seems to be independent of the DNA binding of the GR [130,131].…”