TY - JOUR
T1 - IAPs and RIPK1 mediate LPS-induced cytokine production in healthy subjects and Crohn's disease
AU - Seidelin, Jakob Benedict
AU - Jensen, Simone
AU - Hansen, Morten
AU - de Carvalho Bronze, Mariana Rodrigues
AU - Cuchet-Lourenço, Delphine
AU - Nejentsev, Sergey
AU - LaCasse, Eric Charles
AU - Nielsen, Ole Haagen
N1 - Publisher Copyright: © The Author(s) 2023.
PY - 2024/3/1
Y1 - 2024/3/1
N2 - 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.
AB - 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.
KW - Crohn's disease
KW - human monocyte activation
KW - inhibitor of apoptosis proteins
KW - lipopolysaccharide
KW - receptor-interacting serine/threonine-protein kinase 1
UR - http://www.scopus.com/inward/record.url?scp=85185814267&partnerID=8YFLogxK
U2 - 10.1093/cei/uxad092
DO - 10.1093/cei/uxad092
M3 - Article
C2 - 37583360
SN - 0009-9104
VL - 215
SP - 291
EP - 301
JO - Clinical and experimental immunology
JF - Clinical and experimental immunology
IS - 3
ER -