{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Interleukin‐18 binding protein (IL‑18BP) is an endogenous, high‐affinity inhibitor that plays a central role in regulating the bioactivity of interleukin‑18 (IL‑18), a potent proinflammatory cytokine. By binding IL‑18 in the extracellular space, IL‑18BP prevents its engagement with signalling receptors and thus attenuates downstream inflammatory cascades. For example, loss of IL‑18BP in the gut leads to severe colitis with impaired goblet cell maturation and barrier dysfunction, highlighting its importance in maintaining intestinal homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, IL‑18BP is a key determinant of the effective concentration of free, bioactive IL‑18 in various settings, as only unbound IL‑18 is active; its binding not only neutralizes IL‑18 but also modulates the activity of related cytokines such as IL‑37 by acting as a molecular sink"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the central nervous system, administration of IL‑18BP after traumatic brain injury lowers intracerebral IL‑18 levels and improves neurological recovery."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Similarly, in cardiovascular disease models, IL‑18BP has been shown to prevent left ventricular dysfunction induced by IL‑1β–triggered IL‑18 release, whereas decreased IL‑18BP expression in failing myocardium is associated with increased IL‑18 activity and adverse outcomes"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In colon carcinoma models, interferon‑γ induces IL‑18BP expression in epithelial tumour cells, thereby dampening IL‑18–mediated immune activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Furthermore, in experimental acute kidney injury, overexpression of IL‑18BP curbs macrophage infiltration and chemokine production, contributing to tissue protection"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", and elevated circulating levels of IL‑18BP have been associated with acute coronary syndromes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings underscore the multifaceted role of IL‑18BP in modulating IL‑18–driven inflammation and tissue injury across a diverse range of diseases—including inflammatory bowel disorders, brain trauma, cardiovascular dysfunction, neoplasia, and renal injury—and support its potential utility as a therapeutic target in conditions characterized by excessive IL‑18 activity.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Roni Nowarski, Ruaidhrí Jackson, Nicola Gagliani, et al. 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