Corticosteroid resistance in rheumatoid arthritis: molecular and cellular perspectives.

Corticosteroids are often used to treat a range of chronic autoimmune inflammatory diseases such as asthma, inflammatory bowel disease and rheumatoid arthritis (RA). RA is the most prevalent autoimmune chronic inflammatory rheumatic disorder with a prevalence of 1% in developed nations. 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. This results in a programmed sequence of physiological mechanisms which begin with the release of tumour necrosis factor alpha (TNF ), interleukin-1 (IL-1 ) and IL-6 [3]. 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. Cortisol dampens inflammation by down-regulating the release of TNF , IL-1 and IL-6 whilst MIF and prolactin counteract the effects of cortisol resulting in a balanced inflammatory/immune response [3–5]. 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. At the molecular level, IL-1 , IL-6 and TNF initiate a number of pro-inflammatory intracellular signalling events which include the activation of the transcriptional activities of activator protein-1 (AP-1) and nuclear factorB (NFB) by a phosphorylation-dependent dissociation and/or degradation of Iby specific kinases (Ikinase 1 and 2) in the case of NF-I[7, 8]. 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]. NFis involved in the pathogenesis of inflammation in RA [10]. In addition IL-l and TNF also activate the mitogenactivated protein kinase (MAPK) p38 pathway [11]. MAPK p38 activates the kinases MAPKAPK-2, which in turn targets adenosine/uridine-rich elements (AREs) of pro-inflammatory messenger ribonucleic acids (mRNAs) to bring about their stabilization [9, 12, 13]. IL-l and TNF activate the second wave of cytokine release mechanisms [IL-8, IL-12, IL-15, IL-17, IL-18, interferonand , granulocyte–macrophage colony-stimulating factor (GM-CSF), fibroblast growth factor etc.] that augment the homeostatic signals necessary for the subsequent complex cellular/cytokine cascades of reactions, endothelial activation and enhanced cell adhesion. 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.