Could GILZ Be the Answer to Glucocorticoid Toxicity in Lupus?

Abstract

Glucocorticoids (GC) are used globally to treat autoimmune and inflammatory disorders. Their anti-inflammatory actions are mainly mediated via binding to the glucocorticoid receptor (GR), creating a GC/GR complex, which acts in both the cytoplasm and nucleus to regulate the transcription of a host of target genes. As a result, signaling pathways such as NF-κB and AP-1 are inhibited, and cell activation, differentiation and survival and cytokine and chemokine production are suppressed. However, the gene regulation by GC can also cause severe side effects in patients. Systemic lupus erythematosus (SLE or lupus) is a multisystem autoimmune disease, characterized by a poorly regulated immune response leading to chronic inflammation and dysfunction of multiple organs, for which GC is the major current therapy. Long-term GC use, however, can cause debilitating adverse consequences for patients including diabetes, cardiovascular disease and osteoporosis and contributes to irreversible organ damage. To date, there is no alternative treatment which can replicate the rapid effects of GC across multiple immune cell functions, effecting disease control during disease flares. Research efforts have focused on finding alternatives to GC, which display similar immunoregulatory actions, without the devastating adverse metabolic effects. One potential candidate is the glucocorticoid-induced leucine zipper (GILZ). GILZ is induced by low concentrations of GC and is shown to mimic the action of GC in several inflammatory processes, reducing immunity and inflammation in in vitro and in vivo studies. Additionally, GILZ has, similar to the GC-GR complex, the ability to bind to both NF-κB and AP-1 as well as DNA directly, to regulate immune cell function, while potentially lacking the GC-related side effects. Importantly, in SLE patients GILZ is under-expressed and correlates negatively with disease activity, suggesting an important regulatory role of GILZ in SLE. Here we provide an overview of the actions and use of GC in lupus, and discuss whether the regulatory mechanisms of GILZ could lead to the development of a novel therapeutic for lupus. Increased understanding of the mechanisms of action of GILZ, and its ability to regulate immune events leading to lupus disease activity has important clinical implications for the development of safer anti-inflammatory therapies.

Anorexia nervosa and juvenile lupus erythematosus in a 16-year-old female patient – common disease origin or random coincidence?

“…presented glucocorticoid-induced leucine zipper (GILZ) which is induced by low concentrations of glucocorticoids and produces anti-inflammatory effects and regulates the function of the immune system. As a result, devastating metabolic adverse effects of glucocorticoid therapy could be avoided [ 25 ].…”

Gender May Influence the Immunosuppressive Actions of Prednisone in Young Patients With Inflammatory Bowel Disease

“…An opposite effect of GILZ was observed in oxazolone-induced colitis which is a Th2-dependent model of chronic inflammation where more severe disease was induced in mice overexpressing GILZ compared to the wild type mice suggesting that GILZ could have a protective role in Th1-mediated models of colitis ( 41 ). Further validation studies will help to explore the promising role of GILZ as marker of GC response in IBD patients as already proposed for other pathologies ( 43 , 44 ) evaluating its levels also in the blood cells to avoid an invasive examination.…”

Therapeutic Manipulation of Macrophages Using Nanotechnological Approaches for the Treatment of Osteoarthritis

“…In the clinic, prednisolone, dexamethasone, and others represent well-established treatment options for several rheumatological and orthopaedical pathological conditions, including knee osteoarthritis [ 59 , 60 , 61 ]. Their use in OA is usually restricted to intra-articular injections for short periods, as prolonged treatment with corticosteroids can induce extreme immune suppression, which avoids the resolution of the inflammation [ 62 ] and/or bone resorption in the joint, by impairment of osteoblasts and osteoclasts recruitment [ 63 ].…”