7-12 Dimethylbenz[a]anthracene-induced bone marrow hypocellularity is dependent on signaling through both the TNFR and PKR

摘要: In addition to being carcinogenic, polycyclic aromatic hydrocarbons (PAHs) are known cause deleterious effects on the immune system, including a marked reduction in bone marrow granulocytes and B lymphocytes. The molecular mechanisms underlying hypocellularity incompletely understood. Hematopoiesis is governed by production of cytokines resultant signaling pathways that they initiate. Our hypothesis was PAHs may disrupt cytokine resulting perturbation cellularity observed after PAH administration. TNF-alpha IFN-gamma two involved regulation hematopoiesis. Based observations made previous research, we sought determine if 7-12 dimethylbenz[a]anthracene (DMBA) murine were mediated through actions these molecules. Transgenic mice null for either or receptors injected with DMBA compared wild-type mice. We tumor necrosis factor alpha receptor (TNFR) protected against DMBA-induced hypocellularity, while not. addition, found dsRNA-dependent protein kinase (PKR) also from hypocellularity. PKR an intracellular molecule has been demonstrated be activated TNFR-mediated signaling. Furthermore, upregulation administration dependent TNFR. These results point role TNFR-dependent signaling, operating at least part via activation, as mechanism toxicity.