Uranium induces TNF alpha secretion and MAPK activation in a rat alveolar macrophage cell line

Uranium is a toxic heavy metal found mainly in the nuclear industry, but it is also used in the manufacturing of military munitions. Inhalation studies using animal models have demonstrated that long-term exposure to uranium can lead to the development of neoplasia and fibrosis at the pulmonary level. Because it has been demonstrated that such effects are often associated with inflammation, the effect of uranium on TNFalpha, IL-1beta, and IL-10 synthesis by macrophages was assessed in vitro using the NR8383 cell line. Our results show that a significant TNFalpha secretion was induced by uranium but not by other metals such as gadolinium. However, IL-1beta and IL-10 secretions were unaffected by uranium treatment. TNFalpha secretion was detectable since 50 microM of uranium and was maximal after 24 h of exposure. Determination of the mechanisms of uranium-induced TNFalpha production was assessed through the evaluation of protein kinases activation. Our results showed that uranium treatment induced c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) activation. The use of pharmacological inhibitors suggested that both p38 MAPK and protein kinase C (PKC) participate in the signal transduction of uranium-induced TNFalpha secretion. The regulation of TNFalpha secretion involves TNFalpha mRNA accumulation at least through the stabilization of TNFalpha mRNA, but p38 MAPK did not appear to be involved in this stabilization. However, this observation does not exclude regulation of TNFalpha synthesis at the transcriptional level, which remains to be demonstrated. Taking together, these results suggest that uranium can induce TNFalpha secretion by macrophages, thus contributing to a better understanding of the pathological effect of uranium on the lung.