Back to Search
Start Over
MLN4924 protects against interleukin-17A-induced pulmonary inflammation by disrupting ACT1-mediated signaling.
- Source :
-
American journal of physiology. Lung cellular and molecular physiology [Am J Physiol Lung Cell Mol Physiol] 2019 Jun 01; Vol. 316 (6), pp. L1070-L1080. Date of Electronic Publication: 2019 Mar 20. - Publication Year :
- 2019
-
Abstract
- An excessive inflammatory response in terminal airways, alveoli, and the lung interstitium eventually leads to pulmonary hypertension and chronic obstructive pulmonary disease. Proinflammatory cytokine interleukin-17A (IL-17A) has been implicated in the pathogenesis of pulmonary inflammatory diseases. MLN4924, an inhibitor of NEDD8-activating enzyme (NAE), is associated with the treatment of various types of cancers, but its role in the IL-17A-mediated inflammatory response has not been identified. Here, we report that MLN4924 can markedly reduce the expression of proinflammatory cytokines and chemokines such as IL-1β, IL-6, and CXCL-1 and neutrophilia in a mouse model of IL-17A adenovirus-induced pulmonary inflammation. MLN4924 significantly inhibited IL-17A-induced stabilization of mRNA of proinflammatory cytokines and chemokines in vitro. Mechanistically, MLN4924 significantly blocked the activation of MAPK and NF-κB pathways and interfered with the interaction between ACT1 and tumor necrosis factor receptor-associated factor proteins (TRAFs), thereby inhibiting TRAF6 ubiquitination. Taken together, our data uncover a previously uncharacterized inhibitory effect of MLN4924 on the IL-17A-mediated inflammatory response; this phenomenon may facilitate the development of MLN4924 into an effective small-molecule drug for the treatment of pulmonary inflammatory diseases.
- Subjects :
- Adaptor Proteins, Signal Transducing
Animals
Cell Line
Chemokine CXCL1 biosynthesis
Disease Models, Animal
Humans
Hypertension, Pulmonary pathology
Interleukin-17 metabolism
Interleukin-1beta biosynthesis
Interleukin-6 biosynthesis
Male
Mice
Mice, Inbred C57BL
NF-kappa B metabolism
Pneumonia drug therapy
Pneumonia pathology
Pulmonary Disease, Chronic Obstructive pathology
TNF Receptor-Associated Factor 6 metabolism
Ubiquitination drug effects
Cyclopentanes pharmacology
Enzyme Inhibitors pharmacology
Hypertension, Pulmonary prevention & control
Pneumonia prevention & control
Pulmonary Disease, Chronic Obstructive prevention & control
Pyrimidines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1504
- Volume :
- 316
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Lung cellular and molecular physiology
- Publication Type :
- Academic Journal
- Accession number :
- 30892082
- Full Text :
- https://doi.org/10.1152/ajplung.00349.2018