RIPK1 Mediates TNF-Induced Intestinal Crypt Apoptosis During Chronic NF-κB Activation.
Cell Mol Gastroenterol Hepatol
; 9(2): 295-312, 2020.
Article
en En
| MEDLINE
| ID: mdl-31606566
ABSTRACT
BACKGROUND AND AIMS:
Tumor necrosis factor (TNF) is a major pathogenic effector and a therapeutic target in inflammatory bowel disease (IBD), yet the basis for TNF-induced intestinal epithelial cell (IEC) death is unknown, because TNF does not kill normal IECs. Here, we investigated how chronic nuclear factor (NF)- κB activation, which occurs in human IBD, promotes TNF-dependent IEC death in mice.METHODS:
Human IBD specimens were stained for p65 and cleaved caspase-3. C57BL/6 mice with constitutively active IKKß in IEC (Ikkß(EE)IEC), Ripk1D138N/D138N knockin mice, and Ripk3-/- mice were injected with TNF or lipopolysaccharide. Enteroids were also isolated from these mice and challenged with TNF with or without RIPK1 and RIPK3 inhibitors or butylated hydroxyanisole. Ripoptosome-mediated caspase-8 activation was assessed by immunoprecipitation.RESULTS:
NF-κB activation in human IBD correlated with appearance of cleaved caspase-3. Congruently, unlike normal mouse IECs that are TNF-resistant, IECs in Ikkß(EE)IEC mice and enteroids were susceptible to TNF-dependent apoptosis, which depended on the protein kinase function of RIPK1. Constitutively active IKKß facilitated ripoptosome formation, a RIPK1 signaling complex that mediates caspase-8 activation by TNF. Butylated hydroxyanisole treatment and RIPK1 inhibitors attenuated TNF-induced and ripoptosome-mediated caspase-8 activation and IEC death in vitro and in vivo.CONCLUSIONS:
Contrary to common expectations, chronic NF-κB activation induced intestinal crypt apoptosis after TNF stimulation, resulting in severe mucosal erosion. RIPK1 kinase inhibitors selectively inhibited TNF destructive properties while preserving its survival and proliferative properties, which do not require RIPK1 kinase activity. RIPK1 kinase inhibition could be a potential treatment for IBD.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Colitis Ulcerosa
/
Enfermedad de Crohn
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Apoptosis
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Factor de Transcripción ReIA
/
Proteína Serina-Treonina Quinasas de Interacción con Receptores
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Mucosa Intestinal
Tipo de estudio:
Observational_studies
/
Prognostic_studies
Idioma:
En
Revista:
Cell Mol Gastroenterol Hepatol
Año:
2020
Tipo del documento:
Article