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During the course of evolution, metazoans evolved an innate immune system to protect themselves from invasion by pathogens. Once triggered, this system indiscriminately killed all invaders including bacteria, virally infected cells and parasites in the vicinity.1 This ‘scorched earth’ approach also leads to the death of normal bystander cells of the host; in some cases this damage can be much greater than the volume where the invader is located. The initiation of this innate response is set in motion by immune cells producing and releasing cytokines after recognising pathogen-associated molecular patterns—for example, toll receptor ligands2 and leucine-rich repeats3—as well as endogenous signals such as HMGB1 produced by damaged cells4 interacting with immune competent cells. This latter initiation process can also be set in motion as a result of hypoxia, injury or stress (eg, infarction, trauma, metabolic disturbances) without the presence of an invader, leading to a number of pathological processes that we see today in modern medicine. Two cytokines play major roles in the innate immune response—tumour necrosis factor (TNF) and erythropoietin (EPO). This review will describe their early discovery and their interplay to expand and stop the penumbra of damage.
It is hard today to realise that the role of cytokines in health and disease is a phenomenon that has only been appreciated in the past 30 years. Before that time many different bioactivities were described, but none had been sufficiently characterised to relate a bioactivity with a specific molecular entity. The advent of microsequencing of proteins and cloning of genes allowed, for the first time, the ability to identify a single synthetic protein with a specific biological activity. As it turned out, the recombinant cytokines frequently were found to have many biological activities. This in part explains the disparate names that were given …