Balancing Strategies: GC and GILZ Axis

Glucocorticoids (GC) are universally relied upon for treatment of SLE. Through binding of the glucocorticoid receptor (GR), they initiate a suite of mechanisms that substantially change the behaviour of cells. The GR binds directly to protein targets within the cytoplasm to interrupt their activity, and acts as a transcription factor to alter gene transcription on a scale that produces wholesale changes in the transcriptional output of cells. This results in a return to immunological quiescence that is a critical anchor of rheumatologic treatment, with no current parallels. Devastatingly, however, GC reliably bring about a collection of adverse effects that measurably and substantially contribute to poor outcomes in SLE. A safe alternative, with the same broad effects across cells and pathways of the immune system, is critically needed. Recent research has substantiated the concept that the glucocorticoid-induced leucine zipper (GILZ) protein may represent such an alternative. This chapter discusses the mechanisms utilized by the GR to bring about anti-inflammatory effects in lupus, and the harmful metabolic effects that are caused by GC. It also describes the protective functions of GILZ in comparison to GC, and preliminary evidence that GILZ may not evoke the metabolic pathways that make GC such a double-edged sword in the arsenal of lupus treatment.