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

Jakob Benedict Seidelin*, Simone Jensen, Morten Hansen, Mariana Rodrigues de Carvalho Bronze, Delphine Cuchet-Lourenҫo, Sergey Nejentsev, Eric Charles LaCasse, Ole Haagen Nielsen

*Corresponding author af dette arbejde

Abstract

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.

OriginalsprogEngelsk
TidsskriftClinical and Experimental Immunology
Vol/bind215
Udgave nummer3
Sider (fra-til)291–301
ISSN0009-9104
StatusUdgivet - mar. 2024

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