Abstract
Delayed wound healing is one of the most common secondary adverse effects associated to the therapeutic use of glucocorticoid (GC) analogs, which act through the ligand-dependent transcription factor GC-receptor (GR). GR function is exerted through DNA-binding-dependent and –independent mechanisms, classically referred to as transactivation (TA) and transrepression (TR). Currently both TA and TR are thought to contribute to the therapeutical effects mediated by GR; however their relative contribution to unwanted side effects such as delayed wound healing is unknown. We evaluated skin wound healing in transgenic mice with keratinocyte-restricted expression of either wild type GR or a mutant GR that is TA-defective but efficient in TR (K5-GR and K5-GR-TR mice, respectively). Our data show that at days (d) 4 and 8 following wounding, healing in K5-GR mice was delayed relative to WT, with reduced recruitment of granulocytes and macrophages and diminished TNF-α and IL-1β expression. TGF-β1 and Kgf expression was repressed in K5-GR skin whereas TGF-β3 was up-regulated. The re-epithelialization rate was reduced in K5-GR relative to WT, as was formation of granulation tissue. In contrast, K5-GR-TR mice showed delays in healing at d4 but re-established the skin breach at d8 concomitant with decreased repression of pro-inflammatory cytokines and growth factors relative to K5-GR mice. Keratinocytes from both transgenic mice closed in vitro wounds slower relative to WT, consistent with the in vivo defects in cell migration. Overall, the delay in the early stages of wound healing in both transgenic models is similar to that elicited by systemic treatment with dexamethasone. Wound responses in the transgenic keratinocytes correlated with reduced ERK activity both in vivo and in vitro. We conclude that the TR function of GR is sufficient for negatively regulating early stages of wound closure, while TA by GR is required for delaying later stages of healing.
Highlights
Glucocorticoid (GC) derivatives are widely used as therapeutic agents in acute and chronic inflammatory diseases due to their anti-inflammatory properties [1]
We analyzed the kinetics of healing in K5-GC receptor (GR) and K5-GR-TR mice relative to WT littermates after excision wounds were made on dorsal skin
Immunostaining shows that endogenous GR was mostly localized in the cytoplasm of all epidermal layers and hair follicles (HF) of WT and transgenic mice
Summary
Glucocorticoid (GC) derivatives are widely used as therapeutic agents in acute and chronic inflammatory diseases due to their anti-inflammatory properties [1]. GCs act through the ubiquitously expressed intracellular GC receptor (GR), encoded by a single gene in humans and mice called Nr3c1. Nr3c1 transcripts undergo both alternative splicing and alternative translational initiation, resulting in multiple GR protein isoforms [4]. GRa, which we will refer to as GR, is the predominant mRNA isoform in most cell types and its protein products are able to bind endogenous or synthetic ligands. After binding GCs, GR dissociates from cytoplasmic complexes, dimerizes and translocates to the nucleus, where it modulates gene transcription [5]. GR monomers or dimers can bind to GC-response elements or GREs located in target genes [6]. Besides DNA-binding-dependent transcriptional regulation, GR regulates gene expression by interfering with other transcription factors, such as NF-kB, AP-1 or STATs, without direct binding to DNA [7,8]
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