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2015 ; 16
(1
): 48
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TWEAK enhances TGF-?-induced epithelial-mesenchymal transition in human bronchial
epithelial cells
#MMPMID25890309
Itoigawa Y
; Harada N
; Harada S
; Katsura Y
; Makino F
; Ito J
; Nurwidya F
; Kato M
; Takahashi F
; Atsuta R
; Takahashi K
Respir Res
2015[Apr]; 16
(1
): 48
PMID25890309
show ga
BACKGROUND: Chronic airway inflammatory disorders, such as asthma, are
characterized by airway inflammation and remodeling. Chronic inflammation and
damage to the airway epithelium cause airway remodeling, which is associated with
improper epithelial repair, and is characterized by elevated expression of
transforming growth factor-? (TGF-?). Epithelial-mesenchymal transition (EMT) is
an important mechanism during embryonic development and tissue remodeling whereby
epithelial cells gain the capacity to increase motility by down-regulation of
epithelial markers and up-regulation of mesenchymal markers. TGF-? is a central
inducer of EMT, and TGF-?-induced EMT is enhanced by pro-inflammatory cytokines,
including tumor necrosis factor-? (TNF-?) and interleukin-1?. We investigated
whether the pro-inflammatory cytokine TWEAK (TNF-like weak inducer of apoptosis)
enhanced TGF-?1-induced EMT in the human bronchial epithelial cell line BEAS-2B.
METHODS: Quantitative RT-PCR and western blotting were used to define alterations
in epithelial and mesenchymal marker expression in BEAS-2B cells. The cells were
assessed for 48 h after stimulation with TGF-?1 alone or in combination with
TWEAK. RESULTS: TGF-?1 induced spindle-like morphology and loss of cell contact,
and reduced the expression of epithelial marker E-cadherin and increased the
expression of mesenchymal markers N-cadherin and vimentin. Our data, for the
first time, show that TWEAK reduced the expression of E-cadherin, and that
co-treatment with TGF-?1 and TWEAK enhanced the TGF-?1-induced features of EMT.
Moreover, hyaluronan synthase 2 expression was up-regulated by a combination with
TGF-?1 and TWEAK, but not TNF-?. We also demonstrated that the Smad, p38 MAPK,
and NF-?B signaling pathways, and the transcriptional repressor ZEB2 might
mediate N-cadherin up-regulation by TGF-?1 in combination with TWEAK.
CONCLUSIONS: These findings suggest that the pro-inflammatory cytokine TWEAK and
TGF-?1 have synergistic effects in EMT and may contribute to chronic airway
changes and remodeling.