Abstract
Endogenous glucocorticoids (GCs) are steroid hormones that signal in virtually all cell types to modulate tissue homeostasis throughout life. Also, synthetic GC derivatives (pharmacological GCs) constitute the first-line treatment in many chronic inflammatory conditions with unquestionable therapeutic benefits despite the associated adverse effects. GC actions are principally mediated through the GC receptor (GR), a ligand-dependent transcription factor. Despite the ubiquitous expression of GR, imbalances in GC signalling affect tissues differently, and with variable degrees of severity through mechanisms that are not completely deciphered. Congenital or acquired GC hypersensitivity or resistance syndromes can impact responsiveness to endogenous or pharmacological GCs, causing disease or inadequate therapeutic outcomes, respectively. Acquired GC resistance is defined as loss of efficacy or desensitization over time, and arises as a consequence of chronic inflammation, affecting around 30% of GC-treated patients. It represents an important limitation in the management of chronic inflammatory diseases and cancer, and can be due to impairment of multiple mechanisms along the GC signalling pathway. Among them, activation of the mitogen-activated protein kinases (MAPKs) and/or alterations in expression of their regulators, the dual-specific phosphatases (DUSPs), have been identified as common mechanisms of GC resistance. While many of the anti-inflammatory actions of GCs rely on GR-mediated inhibition of MAPKs and/or induction of DUSPs, the GC anti-inflammatory capacity is decreased or lost in conditions of excessive MAPK activation, contributing to disease susceptibility in tissue- and disease- specific manners. Here, we discuss potential strategies to modulate GC responsiveness, with the dual goal of overcoming GC resistance and minimizing the onset and severity of unwanted adverse effects while maintaining therapeutic potential.
Highlights
As the interactions between GC receptor (GR) and mitogen-activated protein kinases (MAPKs) depend on the affected tissue(s) and are disease-dependent, the following sections have been organized according to the distinct pathologies associated to GC resistance
We demonstrated that the gain-of epidermal GR function resulted in resistance to chemically-induced skin tumors while its loss caused increased sensitivity to develop these tumors [129,130]
Several p38 inhibitors for various uses have been patented, and multiple clinical trials have addressed the use of Jun N-terminal kinases (JNK) and extracellular signal-regulated kinases (ERK) inhibitors, mainly for hematologic malignancies
Summary
In response to pleiotropic signals, including those from inflammatory cytokines, MAPKs dissociate from the MAPK module and can translocate to the nucleus to target TFs such as AP-1 and NF-κB or phosphorylate downstream protein kinases or other substrates to regulate gene expression [42,43] (Figure 2). These kinases are critical in regulating inflammation they play key roles in regulating cell growth, apoptosis, and differentiation.
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