Involvement of p38-βTrCP-Tristetraprolin-TNFα axis in radiation pneumonitis

Abstract

Early release of tumor necrosis factor-alpha (TNF-α) 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-α synthesis, which correlated with increased TNF-α 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-α release and lung inflammation were analyzed at different time points post-irradiation. Ttp−/− mice with elevated (9.5±0.6 fold) basal TNF-α showed further increase (12.2±0.9 fold, p<0.02) in TNF-α 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 (β-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 β-TrCP knockdown, or overexpression of dominant negative Cullin1 mutants protected TTP from radiation-induced degradation. Consequently, SB203580 pretreatment blocked radiation-induced TNF-α release and radioprotected macrophages. Together, these data establish the involvement of the p38-βTrCP-TTP-TNFα signaling axis in radiation-induced lung inflammation and identified p38 inhibition as a possible lung radioprotection strategy.

RNA-binding proteins tristetraprolin and human antigen R are novel modulators of podocyte injury in diabetic kidney disease

“…It has been shown that TTP inhibits inflammatory cytokine production by destabilizing target mRNAs 14,15 while HuR functions oppositely to stabilize cytokine (see figure on previous page) Fig. 5 GSK-3β modulated the expression and function of TTP and HuR.…”

“…Tristetraprolin binds to the AREs of mRNAs encoding multiple inflammatory cytokines and promotes their degradation 13 . For example, TTP inhibits TNF-α synthesis by destabilizing TNF-α mRNA 14,15 and it is upregulated during inflammatory responses to decrease proinflammatory gene expression 16 . We previously reported that urinary and serum levels of TTP are lower in patients with diabetes and clinical proteinuria than in healthy individuals 16 , indicating that TTP might negatively modulate DKD progression.…”

p38 MAPK Inhibition Mitigates Hypoxia-Induced AR Signaling in Castration-Resistant Prostate Cancer

“…Whether this would be more attractive than current second line anti-androgen treatments remains to be seen, and would probably depend on toxicity profiles and co-morbidities. On that note, p38 is well-known to regulate inflammation, and a few studies have suggested that p38 inhibition might mitigate radiation-induced gene expression associated with promotion of inflammation [ 35 , 36 , 37 ]. It would be interesting to assess whether p38 inhibition thereby could offer radioprotection of normal tissues and further widen the therapeutic window in the context of radiotherapy.…”

Captopril reduces lung inflammation and accelerated senescence in response to thoracic radiation in mice

“…The elevation of pro-inflammatory cells in the lung is associated with increased local expression of cytokines and chemokines post-irradiation [ 4 , 13 ]. IL-1β and TNF-α are produced by activated macrophages and are associated with airway hyper-responsiveness and pneumonitis [ 65 , 66 ]. Additionally, TNF-α expression is believed to be important for subsequent fibrosis following radiation exposure [ 13 ].…”