Abstract
Inflammatory cytokines, such as tumor necrosis factor and the members of the interferon family, are potent mediators of the innate anti-viral immune response. The intracellular anti-viral states resulting from treatment of cultured cells with each of these molecules independently has been well studied; but, within complex tissues, the early inflammatory response is likely mediated by simultaneously expressed mixtures of these, and other, protective anti-viral cytokines. Such cytokine mixtures have been shown to induce potently synergistic anti-viral responses in vitro which are more complex than the simple summation of the individual cytokine response profiles. The physiological role of this ‘cytokine synergy’, however, remains largely unappreciated in vivo. This brief commentary will attempt to summarize the potential effects and mechanisms of anti-viral cytokine synergy as well as present several ‘real-world’ applications where this phenomenon might play an important role.
Highlights
Inflammatory cytokines, such as the type-I and type-II interferons (IFNs) and tumor necrosis factor (TNF), are small secreted proteins which, together with their cognate receptors and downstream signaling pathways, play a key role in the innate restriction of invading pathogens such as viruses
Bartee and McFadden including humans and mice, are able to readily control viral infection. In humans this control is mediated by the rapid secretion of multiple cytokines, including TNF and IFNα, from infected myeloid cells, such as macrophages, soon after virus challenge [5]
Cells adjacent to these activated myeloid cells are subjected to a complex milieu made up of multiple cytokines
Summary
Inflammatory cytokines, such as the type-I and type-II interferons (IFNs) and tumor necrosis factor (TNF), are small secreted proteins which, together with their cognate receptors and downstream signaling pathways, play a key role in the innate restriction of invading pathogens such as viruses. In the case of MYXV, none of the individual cytokines identified are sufficient to completely ablate viral replication in primary human cells; the combination of multiple cytokines together induces a unique cellular transcriptional program which displays significantly greater anti-viral effects than treatment with the individual cytokines alone can produce [6]. This “greater than the sum of its parts” response has been observed in a variety of other systems and has been termed ‘cytokine synergy’ [7]. Due to the complexity involved in analyzing the huge number of cytokine combinations that could potentially occur in vivo, the understanding of cytokine synergy has severely lagged behind the study of the anti-viral states induced by the individual proteins
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