IAPs and RIPK1 mediate LPS-induced cytokine production in healthy subjects and Crohn’s disease

• Published in: Clinical and experimental immunology Vol. 215; no. 3; pp. 291 - 301
• Main Authors: Seidelin, Jakob Benedict, Jensen, Simone, Hansen, Morten, de Carvalho Bronze, Mariana Rodrigues, Cuchet-Lourenҫo, Delphine, Nejentsev, Sergey, LaCasse, Eric Charles, Nielsen, Ole Haagen
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 19.02.2024
• Subjects: Carrier Proteins; Crohn Disease; Cytokines - metabolism; Healthy Volunteers; Humans; Inflammation and Inflammatory Disease; Leukocytes, Mononuclear - metabolism; Lipopolysaccharides; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Tumor Necrosis Factor-alpha - metabolism; human monocyte activation; inhibitor of apoptosis proteins; lipopolysaccharide; Crohn’s disease; receptor-interacting serine/threonine-protein kinase 1
• ISSN: 0009-9104; 1365-2249; 1365-2249
• DOI: 10.1093/cei/uxad092

Innate immune activity fuels intestinal inflammation in Crohn’s disease (CD), an inflammatory bowel disease. Identification and targeting of new molecular regulators of the innate activity are warranted to control the disease. Inhibitor of apoptosis proteins (IAPs) regulate both cell survival and inflammatory signaling. We investigated the effects of IAP inhibition by second mitochondria-derived activator of caspases (SMAC) mimetics (SMs) on innate responses and cell death to pathogen-associated molecular patterns in peripheral blood mononuclear cells (PBMCs) and monocytes. IAPs inhibited lipopolysaccharide (LPS)-induced expression of proinflammatory interleukin (IL)-1β, IL-6. Likewise, LPS (but not muramyl dipeptide or Escherichia coli) induced TNF-α was inhibited in CD and control PBMCs. The SM effect was partially reversed by inhibition of receptor-interacting serine/threonine-protein kinase 1 (RIPK1). The effect was mainly cell death independent. Thus, IAP inhibition by SMs leads to reduced production of proinflammatory cytokines and may be considered in the efforts to develop new therapeutic strategies to control CD. LPS/TLR4 signaling in human monocytes goes via cellular inhibitor of apoptosis proteins and involves the scaffolding protein receptor-interacting serine/threonine-protein kinase 1. Inhibition of this pathway by low-dose of clinical candidate Smac mimetics potently reduces cytokine production without causing necroptosis. Moreover, interaction with this LPS-TLR4-cIAP-RIPK1 cascade nearly abolishes lipopolysaccharide-induced cytokine production in Crohn’s disease and might be a future therapeutic target in inflammatory bowel disease. Graphical Abstract Graphical Abstract