Pharmacological inhibition of IKKβ dampens NLRP3 inflammasome activation after priming in the human myeloid cell line THP-1
| Autor: | Andreas Boettcher, Adeline Unterreiner, Muriel Kauffmann, Christopher J. Farady, Jörg Eder, Alice Fruhauf, Ursula Bodendorf, Joëlle Rubert, Diane Heiser, Achim Schlapbach, Frédéric Bornancin, P. Erbel |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Inflammasomes THP-1 Cells Interleukin-1beta Biophysics Caspase 1 Priming (immunology) Thiophenes Biochemistry 03 medical and health sciences 0302 clinical medicine NLR Family Pyrin Domain-Containing 3 Protein medicine Humans THP1 cell line Secretion Protein Kinase Inhibitors Molecular Biology Innate immune system integumentary system Chemistry Kinase NF-kappa B Inflammasome Cell Biology Amides Immunity Innate I-kappa B Kinase Cell biology 030104 developmental biology Nigericin 030220 oncology & carcinogenesis NLRP3 inflammasome complex medicine.drug |
| Zdroj: | Biochemical and Biophysical Research Communications. 545:177-182 |
| ISSN: | 0006-291X |
| Popis: | The NLRP3 inflammasome is a critical component of the innate immune response to sterile inflammation. Its regulation involves a priming step, required for up-regulation of inflammasome protagonists and an activation step leading to NLRP3 inflammasome complex assembly, which triggers caspase-1 activity. The IκKβ kinase regulates canonical NF-κB, a key pathway involved in transcriptional priming. We found that IκKβ also regulates the activation and function of the NLRP3 inflammasome beyond the priming step. Two unrelated IκKβ inhibitors, AFN700 and TPCA-1, when applied after priming, fully blocked IL-1β secretion triggered by nigericin in THP-1 cells. Both inhibitors prevented neither inflammasome assembly, as monitored by measuring the formation of ASC specks, nor the generation of caspase-1 p20, a hallmark of caspase-1 activity, but they impaired the initial cleavage and activation of procaspase-1. These data thus indicate that IκKβ activity is required for efficient activation of NLRP3, suggesting that IκKβ may fulfill a dual role in coupling priming and activation of the NLRP3 inflammasome. |
| Databáze: | OpenAIRE |
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