Glucocorticoid-induced leucine zipper as a context-dependent central integrator of innate and adaptive immune homeostasis.

Glucocorticoid-induced leucine zipper (GILZ) was originally identified as an immediate transcriptional target of glucocorticoid receptor (GR) activation and viewed primarily as a mediator of the anti-inflammatory and immunosuppressive effects of glucocorticoids (GCs). Over the last two decades, this perspective has evolved considerably, and GILZ is now recognized as a widely expressed regulatory protein in most immune cells and many non-immune tissues. In addition to GCs, anti-inflammatory cytokines, including interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), along with metabolic and tissue-derived signals, control GILZ expression. These diverse inputs suggest that GILZ acts within broad physiological networks that extend beyond traditional inflammatory pathways. GILZ's biological activities include regulating cell differentiation, survival, metabolism, tissue repair, and immune responses. Rather than acting through intrinsic enzymatic activity, GILZ exerts its effects mainly through selective interactions with transcription factors and signaling molecules. Through these interactions, it modulates how cells integrate and interpret multiple environmental and intracellular cues, thereby influencing cellular behavior in a context-dependent manner. This review integrates established and emerging evidence into a context-dependent framework for GILZ function across immune and non-immune systems. Rather than defining new functions, it examines how GILZ interactions produce distinct outcomes depending on cellular identity, tissue environment, activation state, and inflammatory timing. Emphasis is placed on immune-cell plasticity, immunometabolic adaptation, tissue homeostasis, inflammation resolution, and their implications for the therapeutic potential and limitations of GILZ modulation. We propose that the biological significance of GILZ is best understood, not as that of a master suppressor of immunity, but as a context-dependent integrator that helps determine how cells transition between inflammatory, regulatory, reparative, and homeostatic states.