Involvement of p38-betaTrCP-Tristetraprolin-TNFalpha axis in radiation pneumonitis
AuthorsKrishnamurthy, Pranathi Meda
Nyati, Mukesh K.
Lawrence, Theodore S.
UMass Chan AffiliationsRNA Therapeutics Institute
Document TypeJournal Article
Respiratory Tract Diseases
MetadataShow full item record
AbstractEarly release of tumor necrosis factor-alpha (TNF-alpha) during radiotherapy of thoracic cancers plays an important role in radiation pneumonitis, whose inhibition may provide lung radioprotection. We previously reported radiation inactivates Tristetraprolin (TTP), a negative regulator of TNF-alpha synthesis, which correlated with increased TNF-alpha release. However, the molecular events involved in radiation-induced TTP inactivation remain unclear. To determine if eliminating Ttp in mice resulted in a phenotypic response to radiation, Ttp-null mice lungs were exposed to a single dose of 15 Gy, and TNF-alpha release and lung inflammation were analyzed at different time points post-irradiation. Ttp-/- mice with elevated (9.5+/-0.6 fold) basal TNF-alpha showed further increase (12.2+/-0.9 fold, p < 0.02) in TNF-alpha release and acute lung inflammation within a week post-irradiation. Further studies using mouse lung macrophage (MH-S), human lung fibroblast (MRC-5), and exogenous human TTP overexpressing U2OS and HEK293 cells upon irradiation (a single dose of 4 Gy) promoted p38-mediated TTP phosphorylation at the serine 186 position, which primed it to be recognized by an ubiquitin ligase (E3), beta transducing repeat containing protein (beta-TrCP), to promote polyubiquitination-mediated proteasomal degradation. Consequently, a serine 186 to alanine (SA) mutant of TTP was resistant to radiation-induced degradation. Similarly, either a p38 kinase inhibitor (SB203580), or siRNA-mediated beta-TrCP knockdown, or overexpression of dominant negative Cullin1 mutants protected TTP from radiation-induced degradation. Consequently, SB203580 pretreatment blocked radiation-induced TNF-alpha release and radioprotected macrophages. Together, these data establish the involvement of the p38-betaTrCP-TTP-TNFalpha signaling axis in radiation-induced lung inflammation and identified p38 inhibition as a possible lung radioprotection strategy.
SourceOncotarget. 2017 Jul 18;8(29):47767-47779. doi: 10.18632/oncotarget.17770. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/40406
RightsCopyright: Krishnamurthy et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Except where otherwise noted, this item's license is described as Copyright: Krishnamurthy et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.