Enhancement of interleukin-4 production in activated CD4+ T cells by diphthalate plasticizers via increased NF-AT binding activity.
BACKGROUND
Diethylhexyl phthalate (DEHP) and diisononyl phthalate (DINP), two commonly used plasticizers in flexible polyvinylchloride formulations, have potentially adverse effects on human health. However, the influence of these diphthalates on allergic responses remains unclear. In this study we examined the effects of DEHP and DINP on IL-4 production in CD4+ T cells and the level of IgE in sera, critical hallmarks associated with allergic diseases.


METHODS
Mouse T cells were exposed to two diphthalates in vitro and in vivo. The levels of IL-4 and IgE were determined by ELISA, and the degree of NF-AT activation was determined by IL-4 gene promoter assay and electrophoretic mobility shift assay.


CONCLUSIONS
Both DEHP and DINP significantly enhanced IL-4 production in activated CD4+ T cells in a concentration-dependent manner. Treatment with DEHP or DINP in vivo resulted in a significant increase of IL-4 production in CD4+ T cells and of IgE levels in sera. Furthermore, DEHP and DINP enhanced the activation of IL-4 gene promoter in EL4 T cells and the enhancing effect mapped to a region in the IL-4 promoter containing binding sites for a transcription factor, NF-AT. The activation of T cells resulted in markedly enhanced binding activities to the NF-AT site, which significantly increased upon addition of DEHP or DINP, indicating that NF-AT was involved in the enhancing effect of DEHP and DINP on IL-4 production. These findings suggest that both DEHP and DINP enhance allergic responses by enhancement of IL-4 production in CD4+ T cells via stimulation of NF-AT-binding activity.
Lee
Mi Hyun
MH
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Kwangju, Republic of Korea.
Park
Jin
J
Chung
Su Wol
SW
Kang
Bok Yun
BY
Kim
Seung Hyun
SH
Kim
Tae Sung
TS
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000187:drug effects*; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D007073:Immunoglobulin E / Q000097:blood / Q000187:drug effects; D015847:Interleukin-4 / Q000096:biosynthesis*; D051379:Mice; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010795:Phthalic Acids / Q000633:toxicity*; D010968:Plasticizers / Q000633:toxicity*; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000187:drug effects*
D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010795:Phthalic Acids; D010968:Plasticizers; D014157:Transcription Factors; D015847:Interleukin-4; D007073:Immunoglobulin E; C012125:diisononyl phthalate; D004051:Diethylhexyl Phthalate