The proximal STAT6 and NF-κB sites are responsible for IL-13-and TNF-α-induced RhoA transcriptions in human bronchial smooth muscle cells

被引:36
作者
Goto, Kumiko [1 ]
Chiba, Yoshihiko [1 ]
Matsusue, Kimihiko [2 ,4 ]
Hattori, Yoshiyuki [3 ]
Maitani, Yoshie [3 ]
Sakai, Hiroyasu [1 ]
Kimura, Shioko [4 ]
Misawa, Miwa [1 ]
机构
[1] Hoshi Univ, Sch Pharm, Dept Pharmacol, Shinagawa Ku, Tokyo 1428501, Japan
[2] Fukuoka Univ, Fac Pharmaceut Sci, Jonan Ku, Fukuoka 8140180, Japan
[3] Hoshi Univ, Sch Pharm, Dept Inst Med Chem, Shinagawa Ku, Tokyo 142850, Japan
[4] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA
关键词
RhoA; STAT6; NF-kappa B; Airway hyperresponsiveness; IL-13; TNF-alpha; NECROSIS-FACTOR-ALPHA; PROTEIN-KINASE-C; CORONARY-ARTERY SPASM; MYOSIN LIGHT-CHAIN; AIRWAY HYPERRESPONSIVENESS; CA2+ SENSITIZATION; CALCIUM SENSITIZATION; EPITHELIAL-CELLS; ASTHMA; INTERLEUKIN-13;
D O I
10.1016/j.phrs.2009.12.001
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
RhoA protein is involved in the Ca2+ sensitization of bronchial smooth muscle (BSM) contraction, and an upregulation of RhoA in BSMs has been suggested in allergic bronchial asthma. However, the mechanism of upregulation of RhoA remains poorly understood. In the present study, the transcriptional regulation of human RhoA gene was investigated in cultured human BSM cells stimulated with IL-13 and TNF-alpha, both of which have an ability to upregulate RhoA protein. Luciferase-based assay showed that the RhoA promoter activity was augmented by both IL-13 and TNF-alpha. The deletion studies revealed a significant level of promoter activity between the 112 bp upstream and the transcription start site, which contains the STAT6 (78-70 bp upstream) and NF-kappa B (84-74 bp upstream) binding regions. The promoter activity was also decreased significantly by the mutations of these regions. Thus, the current study for the first time characterized the transcriptional regulation of the human RhoA gene. The findings also suggest that STAT6 and NF-kappa B are important for the upregulation of RhoA in human BSM induced by IL-13 and TNF-alpha, both of which are major cytokines in the pathogenesis of allergic bronchial asthma. (C) 2009 Elsevier Ltd. All rights reserved.
引用
收藏
页码:466 / 472
页数:7
相关论文
共 46 条
[21]   IL-13-dependent autocrine signaling mediates altered responsiveness of IgE-sensitized airway smooth muscle [J].
Grunstein, MM ;
Hakonarson, H ;
Leiter, J ;
Chen, M ;
Whelan, R ;
Grunstein, JS ;
Chuang, S .
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2002, 282 (03) :L520-L528
[22]   STAT6 mediates eotaxin-1 expression in IL-4 or TNF-α-induced fibroblasts [J].
Hoeck, J ;
Woisetschläger, M .
JOURNAL OF IMMUNOLOGY, 2001, 166 (07) :4507-4515
[23]   Inhibition of myosin phosphatase by upregulated Rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1β [J].
Kandabashi, T ;
Shimokawa, H ;
Miyata, K ;
Kunihiro, I ;
Kawano, Y ;
Fukata, Y ;
Higo, T ;
Egashira, K ;
Takahashi, S ;
Kaibuchi, K ;
Takeshita, A .
CIRCULATION, 2000, 101 (11) :1319-1323
[24]   Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma [J].
Kuperman, DA ;
Huang, XZ ;
Koth, LL ;
Chang, GH ;
Dolganov, GM ;
Zhu, Z ;
Elias, JA ;
Sheppard, D ;
Erle, DJ .
NATURE MEDICINE, 2002, 8 (08) :885-889
[25]   Direct effects of interleukin-13 on signaling pathways for physiological responses in cultured human airway smooth muscle cells [J].
Laporte, JC ;
Moore, PE ;
Baraldo, S ;
Jouvin, MH ;
Church, TL ;
Schwartzman, IN ;
Panettieri, RA ;
Kinet, JP ;
Shore, SA .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2001, 164 (01) :141-148
[26]  
LUKACS NW, 1995, J IMMUNOL, V154, P5411
[27]   Interleukin-13 upregulates eotaxin expression in airway epithelial cells by a STAT6-dependent mechanism [J].
Matsukura, S ;
Stellato, C ;
Georas, SN ;
Casolaro, V ;
Plitt, JR ;
Miura, K ;
Kurosawa, S ;
Schindler, U ;
Schleimer, RP .
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 2001, 24 (06) :755-761
[28]  
Mukai Yasushi, 2001, FASEB Journal, V15, P1062
[29]   Synthesis and evaluation of 2-{[2-(4-hydroxyphenyl)-ethyl] amino} pyrimidine-5-carboxamide derivatives as novel STAT6 inhibitors [J].
Nagashima, Shinya ;
Yokota, Masaki ;
Nakai, Ei-ichi ;
Kuromitsu, Sadao ;
Ohga, Keiko ;
Takeuchi, Makoto ;
Tsukamoto, Shin-ichi ;
Ohta, Mitsuaki .
BIOORGANIC & MEDICINAL CHEMISTRY, 2007, 15 (02) :1044-1055
[30]   Repeated measurement of nasal lavage fluid chemokines in school-age children with asthma [J].
Noah, TL ;
Tudor, GE ;
Ivins, SS ;
Murphy, PC ;
Peden, DB ;
Henderson, FW .
ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY, 2006, 96 (02) :304-310