Glucocorticoid use in rheumatoid arthritis: benefits, mechanisms, and risks.Kozaci; Corticosteroid resistance in rheumatoid arthritis: Corticosteroids are often deca europe jobs to treat a range of chronic autoimmune inflammatory diseases corticosteroids mechanism of action in rheumatoid arthritis as asthma, inflammatory bowel disease and rheumatoid arthritis RA. It is more common in women than men, suggesting that perturbations of the hormonal systems may be involved in disease pathophysiology. The aetiology of the disease is unknown, but the physiological mechanisms of inflammation involved in this disease share common pathways with other inflammatory situations [ 12 ]. However, the reasons why inflammation persists in RA remain unknown but might relate in part to a dysregulation of the interactions between neuroendocrine and immune systems at the onset of acute inflammation [ 2—6 ].
Kozaci; Corticosteroid resistance in rheumatoid arthritis: Corticosteroids are often used to treat a range of chronic autoimmune inflammatory diseases such as asthma, inflammatory bowel disease and rheumatoid arthritis RA.
It is more common in women than men, suggesting that perturbations of the hormonal systems may be involved in disease pathophysiology. The aetiology of the disease is unknown, but the physiological mechanisms of inflammation involved in this disease share common pathways with other inflammatory situations [ 1 , 2 ]. However, the reasons why inflammation persists in RA remain unknown but might relate in part to a dysregulation of the interactions between neuroendocrine and immune systems at the onset of acute inflammation [ 2—6 ].
Acute inflammation can be initiated by a number of inflammatory triggers. These cytokines activate a cascade of reciprocal local and systemic responses which result in increased secretion of corticotrophin-releasing hormone CRH and arginine vasopressin by the hypothalamus and production of adrenocorticotrophic hormone ACTH , prolactin and macrophage migration inhibitory factor MIF by the pituitary gland and cortisol by the adrenal glands. If acute inflammation is not restrained, it enters a chronic phase, a central feature of many chronic autoimmune inflammatory diseases [ 6 ].
Neuroendocrine regulation of immune function is essential for survival during stress or infection and to modulate immune responses in inflammatory disease. Corticosteroids are the main effector endpoint of the neuroendocrine immune response to inflammation. These in turn enhance the production of a whole range of pro-inflammatory cytokines. These transcription factors are targets of action by cortisol and other corticosteroid type drugs [ 9 ]. The body attempts to down-regulate inflammation by increasing corticosteroid production [ 3 ].
Synthetic corticosteroid analogues such as prednisolone have been made and are often used to treat chronic autoimmune inflammatory disease such as RA, asthma and inflammatory bowel disease. They can effectively reduce the parameters of inflammation such as erythrocyte sedimentation rate ESR and C-reactive protein CRP and induce disease remission.
However, in clinical practice, a proportion of patients fail to respond adequately to corticosteroid therapy [ 14—16 ]. On this basis, patients can be divided into corticosteroid sensitive SS and corticosteroid resistant SR subgroups. The underlying mechanisms involved in the SS and SR phenomenon in patients with RA remain unknown but are of considerable therapeutic interest. The mechanisms of action of corticosteroid can be subdivided into genomic and non-genomic effects [ 17 ].
The non-genomic effects which occur very rapidly are either specific or non-specific. These effects include analgesia and inhibition of adhesion molecule expression. The genomic effects are mediated via the corticosteroid receptor CR whose principal functions of transactivation, DNA binding and ligand binding are localized to specific DNA domains [ 9 ]. Alternative splicing of mRNA results in a number of isoforms Fig. However, there are conflicting data refuting this role [ 23 , 24 ].
The CR-P isoform is encoded for by exons 2—7 plus several base pairs from the subsequent intron region [ 26 ]. This isoform lacks the ligand-binding domain and therefore cannot bind corticosteroids. Its function is unknown. CR-A results from excision of exons 5—7, resulting in juxtaposition of exons 8 to 4; its function is unknown [ 26 ]. GRE can mediate both positive and negative corticosteroid effects [ 30 , 31 ] Fig.
Receptor dissociates from the inactive, multi-protein complex. GRE can mediate both positive and negative corticosteroid effects. Histone acetylation is regulated by a balance between the activity of histone acetyltransferases HATs and histone deacetylases HDACs which reverses the process, leading to gene repression [ 44 ]. Corticosteroids also induce apoptosis of lymphocytes and thymocytes, but these effects may be secondary to the inhibition of cytokine growth and proliferation factors.
The activity of the pro-inflammatory kinase cascade systems, such as the extracellular regulated kinase ERK and JNK mitogen-activated kinases MAPKs [ 48—51 ] are modulated by corticosteroids. For instance, it has recently been shown that corticosteroids induce the sustained expression of MAPK phosphatase 1 MKP-1 which inhibits the MAPK signalling pathways by dephosphorylating proteins [ 52 , 53 ].
Corticosteroids induce the production of MKP-1 which potently inactivates phosphorylated MAPK p38 leading to the destabilization of pro-inflammatory mRNAs by corticosteroids [ 52 , 53 , 56 , 57 ]. Finally, corticosteroids also induce the production of lipocortin, an anti-inflammatory protein made by peripheral blood mononuclear cells which mediates a number of corticosteroid effects. The regulation of gene expression also requires an orchestrated and coordinated control of the cross-talk between transcription factors to regulated transcriptional, post-transcriptional, translational and post-translational events.
These mechanisms are all modulated by corticosteroids. The body needs to regulate the biological effects of corticosteroids.
The mechanisms involved in the regulation of corticosteroid effects include alterations in the bioavailability of corticosteroids within the respective microenvironment of the target tissues and counter-regulation by pro-inflammatory cytokines and hormones.
Factors such as route of administration may be important in determining corticosteroid bioavailability and bioactivity. For instance, malabsorption of orally administered steroid may cause a failure to respond to therapy in some patients with small bowel disease given enteric-coated corticosteroid preparations. Nevertheless, corticosteroids pass through the cell membrane well. In humans, BHD exists as two isoenzymes type 1 and type 2 [ 59 ]. The type 2 BHD inactivates cortisol by converting it to cortisone which is not bioactive, whilst the type 1 isoenzyme converts cortisone to cortisol, and thus may amplify the biological activity of corticosteroids [ 59 ].
MIF down-regulates the immunosuppressive effects of corticosteroids [ 5 ]. The exact mechanisms have not been fully characterized. PLA2 is a key target of the anti-inflammatory actions of corticosteroids. MIF regulates IL-2 secretion and T-cell proliferation [ 60 ], which may in part be mediated via increased cellular expression of prolactin [ 4 ]. Essentially, hormones may be divided into anti-inflammatory hormones, such as cortisol and melatonin, and pro-inflammatory hormones, such as CRH, prolactin, arginine vasopressin and substance P [ 3 , 4 , 61 , 62—73 ].
The biological effects of prolactin have been studied more extensively. Prolactin, like MIF, is produced by the pituitary gland and peripheral blood mononuclear cells and antagonizes the effects of corticosteroids in vivo and in vitro [ 4 , 62—65 ]. It is an essential co-mitogen for T and B cells and can activate natural killer NK cells and macrophages [ 57 , 68 ]. Prolactin is essential for IL-2 and IL-2R expression, is an important pre-requisite for T-cell proliferation and enhances gamma-interferon production [ 67 , 69 , 70 ].
At the molecular level, prolactin exerts its effects via prolactin receptors found on macrophages and T and B cells [ 71 ]. The coupling of the hormone to the prolactin receptors activates the JAK family of kinases which in turn phosphorylate and activate STAT5 [ 72—74 ]. This pathway leads to increased levels of AP-1 [ 79 ].
Thus, prolactin modulates corticosteroid responsiveness by enhancing cell proliferation and survival [ 83 ]. Corticosteroids are used to treat a variety of inflammatory conditions which include asthma, inflammatory bowel disease, chronic autoimmune inflammatory renal, skin and rheumatic diseases as well as being part of immunosuppressive therapy regimes for organ transplant rejection and chemotherapy treatment regimes.
The failure of therapeutic corticosteroid doses to inhibit inflammatory disease in a number of conditions such as RA, asthma and inflammatory bowel disease has been intriguing.
In RA patients, this resistance to corticosteroids appears not to be related to disease severity as measured by clinical parameters. Interestingly, it can also be seen in normal individuals [ 14 , 84—86 , 88 ], suggesting that it may be an intrinsic property of the individual [ 14 ] which may, therefore, have a genetic basis. Interestingly, the ALL cells appear to acquire resistance to corticosteroids during therapy, but this could reflect positive selection of steroid-resistant mutant leukaemic cells that fail to undergo apoptosis [ 89 ].
The molecular basis of corticosteroid resistance in RA patients remains largely unknown but may be related in part to perturbations and dysregulation of some of the known cellular and molecular mechanisms of corticosteroid action.
It is not yet clear whether different mechanisms operate in different individuals or diseases or whether the SR phenomenon seen in RA patients is primary or secondary. The SR mechanisms have also been studied in asthma patients who are not responsive to corticosteroids.
Some of the mechanisms observed in asthma patients are of relevance to the phenomenon of corticosteroid resistance seen in some patients with rheumatoid arthritis. In Vingerhoeds et al.
They reported a case of cortisol resistance in which high circulating cortisol blood levels were not associated with Cushing's syndrome but appeared to be related to a ligand affinity defect of the corticosteroid receptor. This family has been re-studied and a defect in the affinity of corticosteroid receptor for cortisol was demonstrated [ 91 , 92 ]. Polymorphic alterations in the CR gene were proposed as the underlying molecular basis of SR in this family.
The term primary SR was coined. In a subsequent study, Huizenga et al. This suggests that alterations somewhere in the cascade of events starting with ligand binding to the receptor, or alterations in the regulation of the expression of corticosteroid responsive genes, or post-receptor defects of interaction with other nuclear factors form the pathophysiological basis of the corticosteroid resistance.
Such a systematic dissection of a genetically based study has not been performed in SR RA patients. Its demonstration has, however, many pathophysiological and therapeutic implications. The SS and SR phenotype appears to be stable when tested repeatedly over time in RA patients and normal subjects, suggesting that it may be an intrinsic property of the individual that is not necessarily acquired as a consequence of prolonged inflammation per se [ 14 ].
Lymphocytes from RA patients have decreased numbers of corticosteroid receptors but this does not result in a significant reduction of cell sensitivity to dexamethasone in vitro [ 94 ]. However, alterations in the expression of the CR isoforms may potentially contribute to a state of reduced corticosteroid responsiveness in patients with RA.
Perturbations of the relative levels of expression of the various chaperone and co-chaperone proteins could potentially contribute to the SR phenomenon. A similar mechanism has been shown for Hsp90 [ ]. The potential role played by defects in these chaperone proteins remains to be determined in RA, but nevertheless, investigation of these modifications in SR RA patients promises to be a particularly rich field for future scientific research.
The functional status of cellular receptors is generally regulated by phosphorylation and nitrosylation mechanisms. Corticosteroid receptors, like other steroid hormone receptors, are phosphoproteins and changes in their phosphorylation status modulate their activity.
Several of the phosphorylation sites lie in the consensus sequences of proline-directed, cell-cycle-associated kinases and MAPK. This supposition is supported by the observation that defects in the phosphorylation of the rat corticosteroid receptor inhibit corticosteroid-dependent gene transcription [ ]. The inhibitory interactions involved in transrepression are mutual see above. Cells from SR asthma patients have been shown to have enhanced AP-1 activity [ ] and phosphorylation of JNK not inhibited by corticosteroids [ ].
In asthma patients, p38 MAPK-induced glucocorticoid receptor phosphorylation reduces its activity and has a role in reduced corticosteroid sensitivity. This may also be of relevance to the SR phenomenon seen in RA. Thus, over-expression of activated STAT5, which could be secondary to prolactin over-expression, diminishes the induction of corticosteroid-responsive genes and contributes to a state of reduced corticosteroid responsiveness.
These mechanisms may be of relevance to the SR phenomenon in RA patients. We are at present investigating these possibilities. MIF inhibits the effects of corticosteroids see above. This might explain the previous observations that: Similar observations have been made in SR asthma patients with respect to IL-2 secretion [ ]. A defect in corticosteroid-induced IL secretion has been observed in SR asthma patients [ ]. The molecular pathways through which corticosteroids act are complex and involve multiple steps involving the cell membrane, steroid receptors, intracellular signalling pathways and interactions with the DNA and RNA machinery.