Approaching the immunophysiology of steroid resistance

Wang and colleagues have investigated a mechanistic basis for resistance to steroid therapy in systemic lupus erythematosus patients. Their examination reveals significant differences in macrophage migration inhibitory factor (MIF)-dependent expression of IκB, which is a critical cellular regulator of the broadly proinflammatory transcription factor NF-κB. Their studies also suggest that MIF may be a clinically useful biomarker in systemic lupus erythematosus and support the therapeutic targeting of MIF as a means to reduce clinical steroid resistance.

In the current issue of Arthritis Research & Th erapy, Wang and colleagues provide functional immunologic data on a molecular pathway for glucocorticoid resistance in systemic lupus erythematosus (SLE) [1]. Gluco corticoids have broad and powerful eff ects on the immune response and, despite the advent of biologic therapies, remain the most important and frequently used immunosuppressive agents in clinical practice [2]. Indeed, if it were not for their dose-limiting toxicity, glucocorticoids in all other respects would be ideal anti-infl ammatory agents: orally absorbed, rapidly acting, and highly eff ective at shutting down a multitude of tissue-damaging, infl ammatory pathways. Despite the clinical success of disease-modifying agents, concomitant steroid use remains an integral part of eff ective therapy as well as an established means for controlling disease exacerbations.
Among practitioners focused on infl ammatory disorders, whether rheumatologic or nonrheumatologic, there has long been the observation that some patients respond poorly to steroids or require high doses and prolonged treatment for disease control. Th ese patients expectedly suff er most from the treatment-related compli cations of glucose intolerance, hypertension, obesity, osteoporosis, and myopathy. Even among patients maintained on low doses, the therapeutic objective remains the absolute minimalization or discontinuation of glucocorticoids. Th is goal has gained additional prominence with the recognition that accelerated atherosclerosis is an attendant consequence of systemic infl ammation and a major cause of morbidity and mortality in rheumatoid arthritis and SLE [3]. Th e contributing eff ects of steroidinduced glucose intolerance and dyslipidemia add to the pathophysiology of atherogenesis and prompt continued investigation into more eff ective steroid-sparing agents and safer approaches to immunosuppression.
Wang and colleagues provide evidence of a specifi c pathway for steroid resistance in patients with treatmentunresponsive SLE [1]. Th e authors investigated the expression and function of the immunoregulatory cytokine macrophage migration inhibitory factor (MIF), which shares a unique regulatory relationship with glucocorticoids, in the peripheral blood monocyte responses of steroid-resistant SLE patients. Experimental work had previously estab lished that MIF counter-regulates the immuno suppres sive action of glucocorticoids on proinfl ammatory cyto kine expression [4]. In human subjects, MIF circu lates in a diurnal rhythm in phase with corticosteroids, but it is rapidly upregulated by stress or infl ammatory stimuli [5]. Indeed, murine MIF was fi rst cloned from activated anterior pituitary cells [6] and a model soon emerged by which MIF, whether released from the neuroendocrine system or the immune system, acts in concert with circulating glucocorticoids to regulate the magnitude of the host infl ammatory response [7]. Mice genetically defi cient in MIF have an alteration in their MIF-gluco corticoid axis and lower glucocorticoid levels, which probably accounts for their developmental defect in alveolar surfactant production and lung maturation [8].
Prior experimental studies have also revealed mechanisms by which MIF counter-regulates the immunosuppressive action of glucocorticoids; these mechanisms Abstract Wang and colleagues have investigated a mechanistic basis for resistance to steroid therapy in systemic lupus erythematosus patients. Their examination reveals signifi cant diff erences in macrophage migration inhibitory factor (MIF)-dependent expression of IκB, which is a critical cellular regulator of the broadly proinfl ammatory transcription factor NF-κB. Their studies also suggest that MIF may be a clinically useful biomarker in systemic lupus erythematosus and support the therapeutic targeting of MIF as a means to reduce clinical steroid resistance. include suppression of glucocorticoid-induced expression of IκBα, which is a cytosolic inhibitor of NF-κB [9], and suppression of glucocorticoid-induced mitogen-activated protein kinase phosphatase [10,11], which inactivates the strongly proinfl ammatory ERK1/2, JNK, and p38 mitogenactivated protein kinase signaling pathways. Wang and colleagues investigated MIF-dependent pathways in two clinically defi ned cohorts of steroid-sensitive and steroidresistant SLE patients. First, they observed increased MIF levels in the steroid-unresponsive patients. Because these subjects may also have more severe underlying disease, this fi nding would be expected [12]. A closer study of peripheral blood monocyte responses, however, revealed higher cytosolic MIF content and higher intranuclear NF-κB levels in the steroid-resistant group. Experimental reduction of MIF expression in turn increased the cytosolic expression of the NF-κB inhibitor, IκB. Conversely, exogenous MIF addition reduced glucocorticoid-induced expression of cytosolic IκB and increased NF-κB expression in the steroid-sensitive patients.
Obtaining such functional data in a signifi cant number of clinically defi ned human subjects is no simple task, as those engaged in studies of human immunologic pathways can attest. One should also appreciate that this MIF-regulated pathway is unlikely to explain all features of glucocorticoid insensitivity; for instance, there is recent evidence that glucocorticoids do not aff ect NF-κB activation within plasmacytoid dendritic cells, which may be important initiators of infl ammation in SLE [13]. Nevertheless, by providing mechanistic information in human cells and validating one pathway suggested by in vitro studies, Wang and colleagues' results have important implications. Th eir data suggest that diff erences in MIF expression may be an intrinsic feature of an individual's immune response, a conclusion also supported by a recent study showing signifi cant associations between SLE clinical severity and commonly occurring, highexpression MIF alleles [14]. Circulating or cytosolic MIF also may be a useful biomarker for steroid resistance. Wang and colleagues further show inhibition of MIFdependent upregulation of IκB by anti-MIF, which is now undergoing clinical evaluation [15]. One may thus envision the contribution of high-expression MIF alleles to the development of steroid resistance and the realistic possibility of a pharmacogenomic approach to this problem based on the utilization of MIF antagonists.

Competing interests
RB is an inventor on patents describing the potential therapeutic utility of MIF inhibition.