Genetic toxicity of cytokines.

Review of the literature shows that such cytokines as human interferons alpha and gamma, tumor necrosis factor alpha, epidermal growth factor and interleukin-2 may exhibit genotoxic properties in human peripheral blood lymphocyte cultures. For all above cytokines, except interleukin-2, parabolic-like relationship between the dose and the frequency of sister chromatid exchanges was found. Although the mechanisms of these genotoxic actions remain largely unknown, generation of free radicals or interaction with enzymes such as DNA topoisomerase II may be suspected. Human interferon alpha also may be considered as an antimutagenic compound in human cells. Human tumor necrosis factor alpha has been reported to enhance cytotoxicity and DNA fragmentation produced by DNA topoisomerase II-targeted anticancer drugs. At the same time, it has some radio- and chemoprotective properties in vitro and in vivo. Despite these facts, the question about genotoxicity of cytokines is not answered. Some problems must be resolved before receiving the final answer. First, much more cytokines must be tested for their genotoxic activity. Second, appropriate test-systems must be designed. Third, genotoxicity studies of cytokines must account for cytokine interaction in the cytokine network as well as for such cytokine-induced effects as cytotoxicity and apoptosis. Fourth, in each case, it is necessary to have experimental evidence that observed genotoxic effects were caused by cytokine under investigation and not by the other factors.