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Significance of the nongenomic, inflammatory pathway in mediating the toxic action of TCDD to induce rapid and long-term cellular responses in 3T3-L1 adipocytes.

TCDD (dioxin) induces a rapid inflammatory response from 3T3-L1 adipocytes as judged by prominent induction of the mRNA expression of prostaglandin-endperoxide synthase 2 (Cox-2) along with other inflammation markers within 1 h. This action of TCDD is clearly antagonized by cell pretreatment with AACOCF3 (an inhibitor of cPLA2), nifedipine (a Ca(2+) channel blocker), or 3'-methyl-4'-nitroflavone (MNF), an antagonist of the Ah receptor (AhR), suggesting the possible involvement of the nongenomic pathway of action of TCDD as shown previously in MCF10A cells [Dong, B., and Matsumura, F. (2008) Mol. Pharmacol. 74 (1), 255-263]. This early inflammatory action of TCDD is clearly different from that mediated by its classical action pathway in that the former is mediated by protein kinases such as PKC, PKA, and tyrosine kinases, but not by ARNT. Furthermore, the former is not blocked by two "DRE-decoy" treatments. Such an inflammatory effect of TCDD on 3T3-L1 adipocyes persists at least for 5 days, when the affected adipocytes exhibit significant reduction in their adipocyte characteristics. To assess the cause for the long-lasting influence of this nongenomic action of TCDD, we tested the effects of AACOCF3, exogenous arachidonic acid (AA), and H89 (an inhibitor of PKA) on the 5 day action of TCDD. These agents clearly antagonized all the long-term actions of TCDD except that on CYP1A1 induction, indicating that the influence of the nongenomic action of TCDD lasts a long time in this cell material. One of the major factors mediating its long-lasting effects has been identified to be PKA.