TY - JOUR
T1 - Transcriptional regulation of VCAM-1 expression by tumor necrosis factor-α in human tracheal smooth muscle cells
T2 - Involvement of MAPKs, NF-κB, p300, and histone acetylation
AU - Lee, Chiang Wen
AU - Lin, Wei Ning
AU - Lin, Chih Chung
AU - Luo, Shue Fen
AU - Wang, Jong Shyan
AU - Pouyssegur, Jacques
AU - Yang, Chuen Mao
PY - 2006/4
Y1 - 2006/4
N2 - Tumor necrosis factor-α (TNF-α) has been shown to induce the expression of adhesion molecules in airway resident cells and contribute to inflammatory responses. Here, the roles of mitogen-activated protein kinases (MAPKs) and NF-κB in TNF-α-induced expression of vascular cell adhesion molecule (VCAM)-1 were investigated in human tracheal smooth muscle cells (HTSMCs). TNF-α-enhanced expression of VCAM-1 protein and mRNA as well as phosphorylation of p42/p44 MARK, p38, and JNK were significantly attenuated by inhibitors of MEK1/2 (U0126), p38 (SB202190), and JNK (SP600125). Transfection with dominant negative mutants of MEK1/2, ERK1, ERK2, p38, and JNK attenuated TNF-α-induced VCAM-1 expression. Furthermore, TNF-α-induced VCAM-1 expression was significantly blocked by a selective NF-κB inhibitor helenalin. TNF-α-stimulated translocation of NF-κB into the nucleus and degradation of IκB-α was blocked by helenalin, but not by U0126, SB202190, or SP600125. VCAM-1 promoter activity was enhanced by TNF-α in HTSMCs transfected with VCAM-1-Luc, which was inhibited by helenalin, U0126, SB202190, and SP600125. Most surprisingly, VCAM-1 expression was also significantly blocked by a selective inhibitor of p300, curcumin. NF-κB transcription factor and p300 were associated with the VCAM-1 promoter, which was dynamically linked to histone H3 acetylation stimulated by TNF-α, as determined by chromatin immunoprecipitation assay. Moreover, the resultant enhancement of VCAM-1 expression increased the adhesion of polymorphonuclear cells (PMNs) to monolayer of HTSMCs, which was blocked by helenalin, U0126, SB202190, or SP600125. These results suggest that in HTSMCs, activation of MAPK pathways, NF-κB, and p300 is essential for TNF-α-induced VCAM-1 expression.
AB - Tumor necrosis factor-α (TNF-α) has been shown to induce the expression of adhesion molecules in airway resident cells and contribute to inflammatory responses. Here, the roles of mitogen-activated protein kinases (MAPKs) and NF-κB in TNF-α-induced expression of vascular cell adhesion molecule (VCAM)-1 were investigated in human tracheal smooth muscle cells (HTSMCs). TNF-α-enhanced expression of VCAM-1 protein and mRNA as well as phosphorylation of p42/p44 MARK, p38, and JNK were significantly attenuated by inhibitors of MEK1/2 (U0126), p38 (SB202190), and JNK (SP600125). Transfection with dominant negative mutants of MEK1/2, ERK1, ERK2, p38, and JNK attenuated TNF-α-induced VCAM-1 expression. Furthermore, TNF-α-induced VCAM-1 expression was significantly blocked by a selective NF-κB inhibitor helenalin. TNF-α-stimulated translocation of NF-κB into the nucleus and degradation of IκB-α was blocked by helenalin, but not by U0126, SB202190, or SP600125. VCAM-1 promoter activity was enhanced by TNF-α in HTSMCs transfected with VCAM-1-Luc, which was inhibited by helenalin, U0126, SB202190, and SP600125. Most surprisingly, VCAM-1 expression was also significantly blocked by a selective inhibitor of p300, curcumin. NF-κB transcription factor and p300 were associated with the VCAM-1 promoter, which was dynamically linked to histone H3 acetylation stimulated by TNF-α, as determined by chromatin immunoprecipitation assay. Moreover, the resultant enhancement of VCAM-1 expression increased the adhesion of polymorphonuclear cells (PMNs) to monolayer of HTSMCs, which was blocked by helenalin, U0126, SB202190, or SP600125. These results suggest that in HTSMCs, activation of MAPK pathways, NF-κB, and p300 is essential for TNF-α-induced VCAM-1 expression.
UR - http://www.scopus.com/inward/record.url?scp=33644916917&partnerID=8YFLogxK
U2 - 10.1002/jcp.20549
DO - 10.1002/jcp.20549
M3 - 文章
C2 - 16288471
AN - SCOPUS:33644916917
SN - 0021-9541
VL - 207
SP - 174
EP - 186
JO - Journal of Cellular Physiology
JF - Journal of Cellular Physiology
IS - 1
ER -