2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces microglial nitric oxide production and subsequent rat primary cortical neuron apoptosis through p38/JNK MAPK pathway

Abstract

It has been widely accepted that microglia, which are the innate immune cells in the brain, upon activation can cause neuronal damage. In the present study, we investigated the role of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in regulating microglial nitric oxide production and its role in causing neuronal damage. The study revealed that TCDD stimulates the expression of inducible nitric oxide synthase (iNOS) as well as the production of nitric oxide (NO) in a dose- and time-dependent manner. Further, a rapid activation of p38 and JNK MAPKs was found in HAPI microglia following TCDD treatment. Blockage of p38 and JNK kinases with their specific inhibitors, SB202190 and SP600125, significantly reduced TCDD-induced iNOS expression and NO production. In addition, it was demonstrated through treating rat primary cortical neurons with media conditioned with TCDD treated microglia that microglial iNOS activation mediates neuronal apoptosis. Lastly, it was also found that p38 and JNK MAPK inhibitors could attenuate the apoptosis of rat cortical neurons upon exposure to medium conditioned by TCDD-treated HAPI microglial cells. Based on these observations, we highlight that the p38/JNK MAPK pathways play an important role in TCDD-induced iNOS activation in rat HAPI microglia and in the subsequent induction of apoptosis in primary cortical neurons.

Keywords: 2,3,7,8-Tetrachlorodibenzo-p-dioxin; 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD); CNS; ERK; IL-6; Inducible nitric oxide synthase (iNOS); JNK; MAPK; Microglia; NO; NOS; Neuron; Nitric oxide (NO); O(2)(*−); ONOO(−); PNS; RNS; ROS; RT-PCR; TCDD; TNF-α; Tumor necrosis factor-alpha; c-Jun N-terminal kinase; central nervous system; eNOS; endothelial nitric oxide synthase; extracellular signal-regulated kinase; iNOS; iROS; inducible nitric oxide synthase; interleukin-6; mitogen-activated protein kinase; nNOS; neuronal nitric oxide synthase; nitric oxide; nitric oxide synthase; p38 MAPK; p38 mitogen-activated protein kinase; p38/JNK MAPK; peripheral nervous system; peroxynitrite; reactive nitrogen species; reactive oxide species; reactive oxygen species; reverse transcription-polymerase chain reaction; superoxide radical.