title: Mono(2-ethylhexyl) phthalate induces both pro- and anti-inflammatory responses in rat alveolar macrophages through crosstalk between p38, the lipoxygenase pathway and PPARalpha.
abstract: Airway inflammation is important in asthma pathogenesis. Recent epidemiological data have indicated an association between asthma symptoms in children and exposure to di(2-ethylhexyl) phthalate (DEHP). Thus, we have studied inflammatory responses in primary rat alveolar macrophages (AMs) after exposure to mono(2-ethylhexyl) phthalate (MEHP), the major primary metabolite of DEHP. First, we show that MEHP induces a dose-dependent release of the pro-inflammatory tumour necrosis factor-alpha (TNF-alpha) in AMs, giving a maximal (5-fold) increase at 0.7 mM. This concentration also induced some cell death. MEHP also induced phosphorylation of MAPK p38, while the p38 inhibitor SB 202190 reduced MEHP-induced TNF-alpha, suggesting a p38-dependent cytokine production. Next, we elucidated possible effects of MEHP on the 5-lipoxygenase (5-LO) pathway and found that MEHP caused increased leukotriene (LTB(4)) release. Further, we found that the 5-LO inhibitor nordihydrogualaretic acid (NDGA) significantly reduced both MEHP-induced TNF-alpha release and MEHP-induced formation of reactive oxygen species (ROS), supporting an involvement of the 5-LO pathway in MEHP induced inflammatory reactions. Last, we found that MK-886, a known inhibitor of peroxisome proliferator-activated receptor alpha (PPARalpha), increased the MEHP-induced TNF-alpha response. This indicates that MEPH-PPARalpha binding mediates an anti-inflammatory signal.
authors: Department of Air Pollution and Noise, Division of Environmental Medicine, Norwegian Institute of Public Health, Oslo, Norway.
authors: Kirsten E
authors: KE
authors: Rakkestad
authors: Jørn A
authors: JA
authors: Holme
authors: Ragnhild E
authors: RE
authors: Paulsen
authors: Per E
authors: PE
authors: Schwarze
authors: Rune
authors: R
authors: Becher
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents; D016923:Cell Death / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects; D002469:Cell Separation; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D007249:Inflammation / Q000139:chemically induced* / Q000473:pathology; D015289:Leukotrienes / Q000096:biosynthesis; D008084:Lipoxygenase / Q000502:physiology*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000473:pathology*; D008297:Male; D047493:PPAR alpha / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011921:Rats, Inbred WKY; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D020239:Receptor Cross-Talk / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000502:physiology*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D015289:Leukotrienes; D047493:PPAR alpha; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D004051:Diethylhexyl Phthalate; D008084:Lipoxygenase; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases