Corticosteroids Resistance Diseases Review

Abstract

Glucocorticoids, the main anti-inflammatory medication, are useful for the treatment of many diseases such as inflammation, respiratory diseases, malignancies, etc., but unfortunately, glucocorticoids cannot inhibit inflammation by various mechanisms. The definition of glucocorticoid resistance is loss of efficacy or reduced sensitization over time and increases due to chronic inflammation. It is affecting 30% of glucocorticoid-treated patients. It shows an essential restriction in the treatment of chronic inflammation and malignancies diseases and can be due to the impairment of various mechanisms along the signaling pathway of glucocorticoids. However, glucocorticoids dissociation has been improved to reduce the SE, DIGRAs “receptor of glucocorticoid dissociation agonists” are a group of trial drugs developed to share various wanted as an anti-inflammatory, suppress immunity, or properties of anti-malignancies of traditional steroids medications with lesser adverse events, but it is so hard to dissociate anti-inflammatory effects from adverse effects. Cases with glucocorticoid unresponsive should use other medications with similar mechanisms in inflammation as well as drugs that may change the molecular mechanism of resistance to glucocorticoid. Here, we discuss the evidence that exists for the hypothesis that individual glucocorticoid resistance underlies the problem.

1. Introduction

Glucocorticoid resistance is the absence of the effect of glucocorticoids and the lack of ability of glucocorticoids to produce an effect on the specific tissue. Two ways might be differentiated, generalized unresponsive in which most tissues are (partly) resistant to glucocorticoids, and some specific tissues resistant to glucocorticoids in which just the impacted tissue escapes cortisol action. To date, widespread glucocorticoid resistance has been found in people in some families, in which most cases were asymptomatic despite too much cortisol production [1, 2].

The clinical variability is described by varying levels of glucocorticoid resistance and the differential sensitivity of the mineralocorticoid and the androgen target tissue. A number of criteria for a diagnostic assessment have been well-defined [2], including indices of cortisol excess without the existence of scientific evidence of Cushing’s syndrome; resistance to glucocorticoid in numerous tissues such as lymphocytes and the pituitary; and finally, maintenance of hypothalamic–pituitary–adrenal (HPA) axis circadian rhythm and responsiveness to stressors in the existence of cortisol excess.

2. Mechanisms of resistance of glucocorticoid

The genes of pro/anti-inflammation could be stimulated or inhibited by glucocorticoids, as well as having post-transcription. Glucocorticoids hinder the many genes of inflammation that are encouraged in prolong inflammatory diseases, such as bronchial constriction (asthma), via reversing acetylation of histone of stimulated genes of inflammation across binding of ligand glucocorticoid receptors (GR) to costimulatory molecules and recruitment of deacetylase-2 of histone (HDAC2) to the encouraged complex of transcription. In high concentration levels of glucocorticoids – glucocorticoid receptor homodimers interact with locations of gene recognition to encourage transcription within increased acetylation of histone of genes of anti-inflammatory and transcription of several genes associated with GCs SE [3].

However, several chronic inflammatory disease patients (Pt) are unresponsive to glucocorticoid agents such as lung fibrosis caused by bleomycin, chronic pulmonary disease (COPD), and cystic fibrosis raised unresponsive to glucocorticoid is observed in cases with lung diseases. Here are many molecular mechanisms of corticosteroid resistance such as hereditary causes that might establish glucocorticoid responsiveness, a number of abnormalities in work of receptor of glucocorticoid have been explained in fibroblasts from cases with familial glucocorticoid resistance [3].

Numerous SNPs (single nuclear polymorphisms) of glucocorticoid receptors have been associated with the alteration of cellular response to glucocorticoids and a polymorphism of glucocorticoid receptor beta is associated with a reduced response of glucocorticoid trans-repression. These polymorphisms have yet to be linked with resistance to glucocorticoids in inflammatory diseases [3].

There are several methods to modify the receptor of glucocorticoid to diminish their efficacy of nuclear translocation and trans-activation. Phosphorylation may occur because of motivation of p38 mitogen-activated protein kinase (MAPK), which may be encouraged by the cytokine’s interleukins such as (IL-2, IL-4, or IL-13), or by MIF (macrophage migration inhibitory factor), of JNK (c-Jun N-terminal kinase) stimulated by pro-inflammatory cytokines or of ERK (extracellular signal-regulated kinase) stimulated by microbial superantigens. In addition, the chronic inflammatory diseases have increased the expression of inducible synthase of NO (iNOS) which produces massive quantities of NO that might encourage glucocorticoid resistance. Also, an increase in the expression of glucocorticoid receptor beta caused by pro-inflammatory cytokines has been observed in glucocorticoid-resistant cases in number of illnesses [3].

In addition, the extreme encouragement of activator protein-1 (AP-1) has been known as a mechanism of glucocorticoid resistance because the activator protein-1 (AP-1) binds glucocorticoid receptor then inhibits its interaction with glucocorticoid receptor element and other transcription factors. Activator protein-1 (AP-1) is a heterodimer of Fos and Jun proteins and might be encouraged by TNF-a (pro-inflammatory cytokines), working within the pathway of c-Jun N-terminal kinase. It describes why the increased inflammation reported in severe inflammatory disease results in secondary glucocorticoid resistance. In elevated c-Jun in de-polymerization of the cytoskeleton, which could also reduce the action of glucocorticoid receptor trans-activating [3].

Cofilin-1 is a depolymerases of actin-binding protein that the cytoskeleton and in gene examinations have been reported as showing increased expression in T-cells from glucocorticoid unresponsive diseases compared to responsive diseases. Thus, the overexpression of cofilin-1 results in glucocorticoid resistance in T-cells [3].

Additionally, one of the most molecular mechanisms of glucocorticoid resistance is abnormal histone acetylation. Acetylation of histone has an essential part in the regulation of inflammatory genes and the mechanism of action of glucocorticoids. Histone deacetylase 2 is significantly decreased in action and expression because of oxidative/nitrative stress so that inflammation becomes resistant to glucocorticoids. The oxygen reactive species also encourages PI3K-delta (phosphoinositide-3-kinase), which causes phosphorylation and deactivation of histone deacetylase 2. So, the oxygen reactive species has an essential mechanism of glucocorticoid resistance and is expanded in most serious and resistance to glucocorticoid diseases [3].

Furthermore, decreased control T cells which cause to decrease in response to glucocorticoid. The interleukine-10 has a role to control the immune cytokine produced by controlling T cells (Treg) in response to glucocorticoids. In decreased glucocorticoid response there is a malfunction of T-helper cells to secrete IL-10 [3].

Also, the inhibitory factor of macrophage migration is a pro-inflammatory cytokine that has strong effects as anti-glucocorticoid and has been associated with various inflammatory diseases. Macrophage migration inhibitory factor has also been involved in glucocorticoid resistance in lung illness [3].

Treatment effects of resistance to glucocorticoid by either selective agonists of the receptor of glucocorticoid (SEGRAs or dissociated steroids) are useful in trans-repression and more effective than trans-activation so have fewer side effects. There are various treatment strategies to control glucocorticoid-unresponsive diseases, but the highly important general methods are to use another anti-inflammatory (“steroid-sparing”) medication or to change the mechanisms of action of glucocorticoid resistance (Figure 1) [3].

Figure 1.

The mechanisms of glucocorticoid resistance.

2.1 Corticosteroids resistance due to the interference between the GR and the MAPK signaling pathways

There is a strong interference between the glucocorticoid receptor and mitogen-activated protein kinase (MAPKs) which normally lead to mutual inhibition. In a given inflammatory context, all sensitivity to glucocorticoids is described by multiple interactions of feedback and feedforward between receptors of glucocorticoids and signaling of cytokine-mediated [4, 5]. While various of the actions of anti-inflammatory of glucocorticoids are reached by the receptor of glucocorticoid-mediated inhibition of the activity of mitogen-activated protein kinase, the anti-inflammatory capacity of glucocorticoid is diminished in conditions of extreme activation of mitogen-activated protein kinase (MAPK) [4, 5, 6]. Given that chronic MAPK/AP-1-/NF-κB activation is a common denominator in multiple inflammatory diseases, the pharmacological inhibition of a particular MAPK signaling pathway has become an add-on strategy intended to restore the sensitivity of GC [7, 8]. As the interferences between the glucocorticoid receptor and MAPK depend on the affected tissue(s) and are thus disease-dependent, the following sections have been organized according to the distinct pathologies associated with resistance of GC [9].

3. Respiratory diseases

Respiratory diseases such as asthma, COPD (chronic obstructive pulmonary disease), and pulmonary fibrosis.

3.1 Asthma

Severe cases of asthma are less responsive to corticosteroids than mild cases of asthma, and therefore steroid resistance may be a mechanism contributing to asthma severity. Asthmatic cases who smoke cigarettes also have a reduced response to inhaled corticosteroids (ICSs) and oral corticosteroids, as well as having more severe asthma, a more rapid reduction in the function of the lung with time, and increased cause of death. The acute severe cases of asthma, glucocorticoid resistance relates to elevated levels of pro-inflammatory cytokines with raised expression and the p38 α and β isoforms activity, relative to GC-responsive individuals [10, 11]. The expanded cytokines levels in alveolar macrophages from asthmatic cases with diminished sensitivity to glucocorticoids (GC) lead to stop receptor of glucocorticoid function across its phosphorylation by p38α as well as the reduced induction of DUSP1 by GCs. In chronic pulmonary cases and smoking asthmatics cigarette smoke produces oxygen reactive species (acting through the formation of peroxynitrite) and in acute asthma and COPD intense inflammation generates oxidative stress to impair the activity of HDAC2 histone deacetylase 2. This not only amplifies the inflammatory response to NF-κB activation but also reduces the effect of corticosteroids as anti-inflammatory, as histone deacetylase 2 is now unable to reverse histone acetylation [12].

Subsequent studies revealed that corticosteroids do not inhibit interleukin-2 (IL-2) and interferon-gamma (IFN-g) levels in some cases. Cases with acute bronchial asthma whose clinical manifestations are uncontrolled with maximum amounts of steroid inhalers also display a smaller number of steroids as inhibitory effects on the production of cytokines and chemokines of peripheral monocytes and alveolar macrophages than seen in responsive cases of asthma. In addition, cases with cortico-steroid-unresponsive asthma also show decreased skin blanching response to non-systemic corticosteroids, indicating that there may be a generalized abnormality in anti-inflammatory sensitivity to corticosteroids in these cases (Figure 2) [12].

Figure 2.

Corticosteroid resistance in cases of severe asthma and COPD.

3.2 COPD

Chronic obstructive pulmonary disease (COPD) is an inflammatory and irreversible pulmonary disorder that is characterized by inflammation and airway destruction. According to general evidence displayed that there are raised the contents of interleukin-8, MMP-9, phosphoinositide 3-kinase delta, MIF, and glucocorticoids receptor-beta in corticosteroid unresponsive cases than in steroid-responsive cases. In difference, the actions of MAPK phosphatase and histone deacetylase 2 (HDAC2) and mitogen-activated protein kinase phosphatase 1 are attenuated in steroid-resistant cases. Therefore, the inflammation does not significantly contribute to the pathogenesis of the chronic pulmonary disease, but it also produces steroid resistance. Neutrophils, lymphocytes, and macrophages contribute to the cause of steroid resistance [13]. Thus, these cells are potential cell goals for molecular treatment in overcoming steroid resistance. p38α also has a significant role in the pathobiology of chronic pulmonary disease, and its stimulation seems critical for glucocorticoid resistance. While p38 targeting in animal models of chronic pulmonary disease was successful, the outcomes of clinical trials evaluating suppression of p38 for chronic pulmonary disease treatment have been so far disappointing. Presently, the extremely encouraging strategy for the treatment of pulmonary diseases such as bronchial asthma or chronic pulmonary disease depends on the use of inhibition of mitogen-activated protein kinase as add-on therapies to inhaled corticosteroids or BB. A selective p38 inhibitor (GW856553) was described to potentiate inhibition of pro-inflammatory cytokines by glucocorticoids in PBMCs from chronic pulmonary disease cases due to the reduced phosphorylation of glucocorticoid receptor-S211, mediated by p38 [9].

3.3 Pulmonary fibrosis

Nettelbladt and Langenbach reported that there was no effect of MP (methylprednisolone) treatment on bleomycin-caused lung fibrosis in mice models. Also, prednisolone treatment had a partial impact on bleomycin-caused lung fibrosis in animal models [14, 15]. The transforming growth factor-beta is significant to pulmonary inflammation and pulmonary fibrosis. Then corticosteroid treatment administered in the last stages of the disease would likely not hinder the transforming growth factor-beta secretion by alveolar macrophages [16].

The relative resistance to corticosteroid treatment in pulmonary fibrosis seen in several lung diseases patient may be induced by the corticosteroid insensitivity of transforming growth factor-beta secretion by alveolar macrophages. This suggests that the glucocorticoid is effective only in early stages of inflammation [17, 18]. However, at an advanced stage when alveolar macrophages are stimulated to produce the transforming growth factor-beta, thus corticosteroids are useless. Stimulated alveolar macrophages obtained after bleomycin-induced pulmonary injury produced large amounts of the transforming growth factor-beta. Furthermore, the alveolar macrophage secretion of the transforming growth factor-beta is not suppressed by the maximum concentrations of corticosteroids [16]. Hosoya T. and colleagues reported that no effect of corticosteroid in pulmonary inflammation and fibrotic response caused by bleomycin due to of elevated level of IL-4 and was resistant to nonselective glucocorticoid after administration (1 mg/kg/day) in animal model [19]. Also, the interleukin-13-mediated myofibroblast differentiation was not inhibited by corticosteroids [20]. Alghamdi and her colleague found that the corticosteroid has a negative effect on the expression of integrins β3 and β6 in pulmonary fibrosis models and the glucocorticoid has not reduced the edema in lung after 28 days. Also, they found that the corticosteroid was effective in early inflammation but was not effective in advance stage of pulmonary fibrosis based on the histology and immunochemical staining [21].

3.4 Leukemias

Steroids are the most medication used as therapeutic agents for the treatment of all malignancies, such as leukemias, lymphomas, and multiple myeloma, due to their properties of immunosuppressive and anti-inflammatory. Many studies using different cell lines derived from malignancies of human hematology showed that inhibitors of ERK and JNK might restore response to glucocorticoids [22].

The absence-of function mutations, polymorphisms, or downregulation of epigenetics of the gene of NR3C1, glucocorticoids unresponsive in leukemia is commonly caused by changes in other pathways of signal and downstream goals. Indeed, glucocorticoids unresponsive in ALL is consistently linked with changes in the control of programmed cell death, including abnormal expression of Bcl2 family members, deactivation of the tumor suppressor TP53, or overexpression of its suppressor, MDM2. It can also include variations in other transduction signaling pathways including Notch, IL7R/JAK/STAT, phosphatase, and tensin homolog/phosphoinositide 3-kinases/protein kinase b/mammalian target of rapamycin and RAS/mitogen-activated protein kinases. As the apoptotic-related mechanisms of glucocorticoid resistance in immune cells (Figure 3) [23].

Figure 3.

Molecular mechanisms of glucocorticoid resistance in T-ALL.

4. Autoimmune diseases

Autoimmune diseases such as rheumatoid arthritis and inflammatory bowel diseases (IBD) exhibit diminished efficacy to routine treatments with glucocorticoids.

4.1 Rheumatoid arthritis “RA”

The prevalence of RA is about 0.5–1% of the population, it is a chronic systemic autoimmune disease. The elderly are high risk, in particular females. Among the proteins involved in glucocorticoid resistance, the pro-inflammatory protein MIF, which raises the creation of pro-inflammatory cytokines and positively controls mitogen-activated protein kinase (MAPK) activation, and GILZ, play major roles. The mechanism by which MIF increases mitogen-activated protein kinase (MAPK) phosphorylation involves the suppression of dual specificity protein phosphatase 1 (DUSP1), thus counteracting the effects of anti-inflammatory glucocorticoids [24]. The overexpression of glucocorticoid-induced leucine zipper in endothelial cells decreased adhesion and inflammation by raising the expression of dual specificity protein phosphatase 1 along with suppression of the tumor necrosis factor-induced activation of all mitogen-activated protein kinases [25]. Essentially, MIF-mediated suppression of dual specificity protein phosphatase 1 needs glucocorticoid-induced leucine zipper, exemplifying how feedforward and feedback loops are responsible for modulating the sensitivity to glucocorticoids [24]. These multiple control mechanisms also highlight the significance of the pathway of MAPK/DUSP, as the decrease of dual specificity protein phosphatase 1 (DUSP1) – either due to raised amounts of MIF or deficiency of glucocorticoid-induced leucine zipper (GILZ) – amplifies MAPK-mediated signaling.

4.2 Inflammatory bowel diseases

There are chronic diseases such as Crohn’s disease and ulcerative colitis which are linked with uncontrol immune response in mucosa of intestine. Glucocorticoids are prescribed as the major anti-inflammatory treatment in cases with moderate to severe disease. While around half of patients respond to glucocorticoid therapy, approximately 30% exhibit partial responses, and 20% are GC-resistant. Also, upon long-term therapy, around 20% of inflammatory bowel disease patients become dependent, requiring glucocorticoids to continue remission [26].

The mechanisms underlying glucocorticoids resistance in inflammatory bowel diseases include elevated levels of cytokines, such as TNFα, IL-6, and IL-8, and low IL-10, in steroid-resistant comparative to steroid sensitive, with activation of the mitogen-activated protein kinase (MAPK) /AP-1 and nuclear factor κB (NF-κB) pathways. Macrophage inhibitory factor (MIF) is also implicated in the pathogenesis of ulcerative colitis through activation of cytokines and subsequent effects of anti-steroid [27]. As most cytokines are goals of main pro-inflammatory linked TFs, this scenario constitutes an auto-amplification loop for glucocorticoids resistance.

5. Conclusion

Many diseases are resistant to corticosteroids with explanation of resistance but mainly molecular mechanism of this resistance is the activation of the mitogen-activated protein kinases (MAPKs) and/or alterations in expression of their regulators, the dual-specific phosphatases (DUSPs), transforming growth factor-beta.

Acknowledgments

First, thanks to Allah for the blessings and help. Then, I would like to thank all those people who shared me their knowledge and experiences and supported me.

I wish to thank my committee members who were more than generous with their expertise and precious time.

A special feeling of gratitude to my parents, my husband, my daughter, my sister, and my brothers who encouraged me and pushed me to do my best.

My parents and my husband have never left my side and always support me.

Conflict of interest

The authors declare no conflict of interest.