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2018 ; 11
(3
): 741-751
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Noxa/HSP27 complex delays degradation of ubiquitylated IkB? in airway epithelial
cells to reduce pulmonary inflammation
#MMPMID29363670
Zhang C
; Jones JT
; Chand HS
; Wathelet MG
; Evans CM
; Dickey B
; Xiang J
; Mebratu YA
; Tesfaigzi Y
Mucosal Immunol
2018[May]; 11
(3
): 741-751
PMID29363670
show ga
IFN-? is known as a pro-inflammatory cytokine, but can also block inflammation in
certain chronic diseases although the underlying mechanisms are poorly
understood. We found that IFN-? rapidly induced Noxa expression and that extent
of inflammation by repeated house dust mite exposure was enhanced in noxa(-/-)
compared with noxa(+/+) mice. Noxa expression blocked transforming necrosis
factor alpha (TNF-?)-induced nuclear translocation of nuclear factor
kappa-light-chain-enhancer of activated B cells (NF-?B) and the production of
pro-inflammatory cytokines. Noxa did not affect TNF-?-induced I?B?
phosphorylation but the degradation of 48-chain-ubiquitylated I?B?. The Cys25 of
Noxa was cross-linked with Cys137 of phospho-HSP27 and both proteins were
required for blocking the degradation of ubiquitylated I?B?. Because
phospho-HSP27 is present in airway epithelial cells and not in fibroblasts or
thymocytes, we generated transgenic mice that inducibly expressed Noxa in airway
epithelia. These mice showed protection from allergen-induced inflammation and
mucous cell metaplasia by blocking nuclear translocation of NF-?B. Further, we
identified a Noxa-derived peptide that prolonged degradation of
48-chain-ubiquitylated I?B?, blocked nuclear translocation of NF-?B, and reduced
allergen-induced inflammation in mice. These results suggest that the
anti-inflammatory role of the Noxa protein may be restricted to airway epithelial
cells and the use of Noxa for therapy of chronic lung diseases may be associated
with reduced side effects.