An emphasis on molecular mechanisms of anti-inflammatory effects and glucocorticoid resistance

Abstract

Glucocorticoids (GC) are universally accepted agents for the treatment of anti-inflammatory and immunosuppressive disorders. They are used in the treatment of rheumatic diseases and various inflammatory diseases such as allergy, asthma and sepsis. They bind with GC receptor (GR) and form GC-GR complex with the receptor and exert their actions. On activation the GC-GR complex up-regulates the expression of nucleus anti-inflammatory proteins called as transactivation and down-regulates the expression of cytoplasmic pro-inflammatory proteins called as transrepression. It has been observed that transactivation mechanisms are notorious for side effects and transrepressive mechanisms are identified for beneficial anti-inflammatory effects of GC therapy. GC hampers the function of numerous inflammatory mediators such as cytokines, chemokines, adhesion molecules, arachidonic acid metabolites, release of platelet-activating factor (PAF), inflammatory peptides and enzyme modulation involved in the process of inflammation. The GC resistance is a serious therapeutic problem and limits the therapeutic response of GC in chronic inflammatory patients. It has been observed that the GC resistance can be attributed to cellular microenvironment changes, as a consequence of chronic inflammation. Various other factors responsible for resistance have been identified, including alterations in both GR-dependent and GR-independent signaling pathways of cytokine action, hypoxia, oxidative stress, allergen exposure and serum-derived factors. The present review enumerates various aspects of inflammation such as use of GC for treatment of inflammation and its mechanism of action. Molecular mechanisms of anti-inflammatory action of GC and GC resistance, alternative anti-inflammatory treatments and new strategy for reversing the GC resistance have also been discussed.

Ginsenoside Rg1 attenuates ultraviolet B-induced glucocortisides resistance in keratinocytes via Nrf2/HDAC2 signalling

“…This phenomenon may be explained by (i) increased Rg1-mediated GR transcriptional repression or (ii) reduced Rg1-mediated GR deacetylation via HDAC2 up-regulation. A reduction in GR levels is one of the mechanisms that contributes to GC resistance2. We also found that Rg1 up-regulated GR expression, which might be explained by the effects of deacetylation on ubiquitin and protein binding, resulting in the loss of selective GR degradation1244.…”

“…Therapeutic strategies to restore GR levels are urgently needed to overcome the challenge of GC resistance240. In this study, we demonstrated that the ginsenoside Rg1 effectively reversed UVB-induced Dex insensitivity by up-regulating the GR and that these effects were partially mediated by the Nrf2/HDAC2 pathway.…”

“…However, the efficacy of glucocorticoids is affected by multiple factors, including oxidative stress, hypoxia, cytokines, changes in the cellular environment, immunomodulation and so on2. A number of reports have demonstrated that oxidative stress plays an important role in glucocorticoid insensitivity by inhibiting the expression and activity of histone deacetylase 2 (HDAC2)34.…”

The Inflammatory Actions of Coagulant and Fibrinolytic Proteases in Disease

“…Synthetic glucocorticoids (GCs) are the most effective anti-inflammatory therapy for disease including rheumatic diseases, allergy, asthma, and sepsis. However, GC resistance limits the therapeutic response of GCs in certain chronic inflammatory diseases including severe asthma, IPF, and cancer [ 104 ]. GC resistance has been attributed to cellular microenvironment changes, that is, alterations in the ECM, as a consequence of chronic inflammation [ 105 ].…”

Epigenetic and Glucocorticoid Receptor-Mediated Regulation of Glutathione Peroxidase 3 in Lung Cancer Cells

“…Because of their potent pro-apoptotic and anti-inflammatory properties and capability to reduce nausea and acute toxicity in normal tissues, GCs have been widely used as components of chemotherapy regimens for treatment of leukemias, lymphomas, and myelomas ( Kim et al, 2004 ). Although GPx3 was not identified in profiling of primary GR target genes by chromatin immunoprecipitation (ChIP) ( Polman et al, 2012 ; Wang et al, 2004 ), we decided to further investigate the role of GCs in the regulation of GPx3 expression because the activated GC-GR complex up-regulates the expression of anti-inflammatory proteins in the nucleus ( Ingawale et al, 2015 ), and because GPx3 is a strong tumor suppressor in many types of cancers. Our findings demonstrate that GR can increase GPx3 expression in lung cancer, suggesting that the GPx3 promoter might be a direct target of GC-mediated signaling in tumor cells.…”