Characterization of the pattern of the nongenomic signaling pathway through which TCDD-induces early inflammatory responses in U937 human macrophages

2,3,7,8-Tetrachlorodibenzo(p)dioxin (TCDD) has been known to induce inflammatory signaling in a number of cell types and tissues. We found that in U937 macrophages TCDD causes rapid activation of cytosolic phospholipase A2 (cPLA2) within 30 min as judged by the increase in the serine 505 phosphorylated form of cPLA2 protein and the increased cellular release of free arachidonic acid. This initial action of TCDD is accompanied with the up-regulation of an important inflammation marker, COX-2 mRNA expression within 1 h, and by 3 h, several other markers become up-regulated. These effects appear to be dependent on the initial increase in the intracellular concentration of Ca²⁺, and activation of cPLA2 and COX-2. A comparative study among three different human cell lines showed that activation of COX-2 within 1 h of action of TCDD is a common feature exhibited by all cell lines. On the other hand, the U937 macrophage line appears to be unique among them with respect to its ability to activate TNF-α and IL-8 mRNA expressions, and not requiring Src kinase in propagating the initial signaling of cPLA2. Based on the rapidity of activation of cPLA2 and COX-2, which occurs within 1 h of cell exposure to TCDD, when no change in mRNA expression of CYP1A1 has been observed, it is apparent that this unique action of TCDD is carried out through a distinct “nongenomic” pathway which, is clearly discernable from the classical, “genomic” action pathway of the AhR by not requiring the participation of ARNT.     

Oxidative stress, endothelial dysfunction and inflammatory response in rat heart to NO₂ inhalation exposure

Epidemiological studies suggest that NO₂ inhalation is associated with adverse effects on heart-related health, however, existing experimental data lack relevant evidences. In this study, a role for oxidative stress, endothelial dysfunction and inflammatory responses in the heart of rats treated with different concentrations of NO₂ (0, 5, 10 and 20 mg m⁻³) was investigated. Mild heart pathology occurred after 7-d exposure (6 h d⁻¹). Marked oxidative stress were induced as evaluated by reduction/induction of antioxidants (Cu/Zn-SOD, Mn-SOD and GPx) activity and increasing formation of MDA and PCO. Also, mRNA and protein biomarkers of vasoconstriction (ET-1, eNOS) and inflammation (TNF-α, IL-1β and ICAM-1) were up-regulated, and p53 mRNA expression, bax/bcl-2 ratio and the mean number of TUNEL-positive myocytes were increased as well. All the results implicate that NO₂ exerted injuries to mammals’ heart, and the damage mechanisms were possibly associated with oxidative stress, endothelial dysfunction and inflammation.