Apigenin Inhibits the Expression of IL-6, IL-8, and ICAM-1 in DEHP-Stimulated Human Umbilical Vein Endothelial Cells and In Vivo Jia Wang, 1 Yanyan Liao, 1 Jianglin Fan, 2 Ting Ye, 1 Xia Sun, 1 and Sijun Dong 1,3 Abstract—Di-(2-ethylhexyl) phthalate (DEHP) in house dust is associated with asthma and allergic inflammatory symptoms in children. This study aimed to examine an inhibitory effect of a flavonoid apigenin on DEHP-stimulated inflammatory responses in human umbilical vein endothelial cells (HUVECs). We found that apigenin significantly suppressed DEHP-stimulated expression of inte- rcellular adhesion molecule-1 (ICAM-1) at the mRNA and protein levels and subsequently inhibited the adhesion of THP-1 monocytic cells to HUVECs. Treatment with apigenin also led to a dose- dependent inhibition of mRNA and protein expression of interleukin (IL)-6 and IL-8 in DEHP- stimulated HUVECs. Moreover, pretreatment with apigenin partially inhibited the DEHP-induced activation of c-Jun N-terminal kinase (JNK) but not the degradation of IκBα or the phosphorylation of extracellular-regulated kinase (ERK)1/2, indicating that the inhibitory effect of apigenin on the expression of IL-6, IL-8, and ICAM-1 may be mediated by JNK pathway but not IκBα/nuclear factor-κB or ERK/mitogen-activated protein kinase pathway. Furthermore, apigenin reduced the release of IL-6, IL-8, and ICAM-1 and inhibited compound 48/80-induced systemic anaphylaxis in vivo. These results suggest that apigenin can be used as a therapeutic means for the treatment of DEHP-associated allergic disorders. KEY WORDS: interleukin-8; interleukin-6; NF-κB; ERK1/2; JNK; intercellular adhesion molecule-1. INTRODUCTION Recent epidemiological studies revealed that ex- cess indoor exposure to phthalates including di-(2- ethylhexyl) phthalate (DEHP) increases the allergic respiratory diseases such as rhinitis and asthma, especially among children and young adults [1, 2]. As the most worldwide plasticizer, DEHP has been used for various plastics such as polyvinyl chloride, building materials, and medical devices [3]. DEHP has been reported to potentiate the inflammatory immune responses through the induction of pro-inflammatory mediators such as interleukin (IL)-4, IL-6, COX-2, and TNF-α in vitro and in vivo [4, 5]. Furthermore, we demonstrated that DEHP treatment could stimulate the production of intercellular adhesion molecule-1 (ICAM-1) and IL-8 in human umbilical vein endothelial cells (HUVECs) [6]. Endothelial cells represent an essential part of the immune system for the participation in immunoregula- tory and inflammatory events [7]. Pro-inflammatory cytokines and adhesion molecules expressed by endo- thelial cells are increased in response to inflammatory stimuli thereby playing an important role in the pathogenesis of allergic inflammation [8]. Previous reports showed that the TNF-α-induced expression of cytokines and ICAM-1 was associated with an increase 1 Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021( Fujian Province, People’ s Republic of China 2 Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi 409-3898, Japan 3 To whom correspondence should be addressed at Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, Fujian Province, People’ s Republic of China. E-mail: sjdong@iue.ac.cn 0360-3997/12/0400-1466/0 # 2012 Springer Science+Business Media, LLC Inflammation, Vol. 35, No. 4, August 2012 ( # 2012) DOI: 10.1007/s10753-012-9460-7 1466