Cytokines in radiobiological responses: a review

Abstract

Cytokines function in many roles that are highly relevant to radiation research. This review focuses on how cytokines are structurally organized, how they are induced by radiation, and how they orchestrate mesenchymal, epithelial and immune cell interactions in irradiated tissues. Pro-inflammatory cytokines are the major components of immediate early gene programs and as such can be rapidly activated after tissue irradiation. They converge with the effects of ionizing radiation in that both generate free radicals including reactive oxygen and nitrogen species (ROS/RNS). "Self" molecules secreted or released from cells after irradiation feed the same paradigm by signaling for ROS and cytokine production. As a result, multilayered feedback control circuits can be generated that perpetuate the radiation tissue damage response. The pro-inflammatory phase persists until such times as perceived challenges to host integrity are eliminated. Antioxidant, anti-inflammatory cytokines then act to restore homeostasis. The balance between pro-inflammatory and anti-inflammatory forces may shift to and fro for a long time after radiation exposure, creating waves as the host tries to deal with persisting pathogenesis. Individual cytokines function within socially interconnected groups to direct these integrated cellular responses. They hunt in packs and form complex cytokine networks that are nested within each other so as to form mutually reinforcing or antagonistic forces. This yin-yang balance appears to have redox as a fulcrum. Because of their social organization, cytokines appear to have a considerable degree of redundancy and it follows that an elevated level of a specific cytokine in a disease situation or after irradiation does not necessarily implicate it causally in pathogenesis. In spite of this, "driver" cytokines are emerging in pathogenic situations that can clearly be targeted for therapeutic benefit, including in radiation settings. Cytokines can greatly affect intrinsic cellular radiosensitivity, the incidence and type of radiation tissue complications, bystander effects, genomic instability and cancer. Minor and not so minor, polymorphisms in cytokine genes give considerable diversity within populations and are relevant to causation of disease. Therapeutic intervention is made difficult by such complexity; but the potential prize is great.

Fig. 1

Cytokines drive the formation of inflammatory lesions working together with DAMPS to generate a pro-inflammatory, pro-oxidant microenvironment. The vasculature becomes leaky, allowing infiltration by neutrophils, and then macrophages and lymphocytes that migrate along chemokine gradients. Acute phase proteins, including cytokines, are generated along with a fair measure of cell death. In the periphery, cells may become more resistant to death and infection. Hypoxia may occur and in time the lesion resolves under the influence of anti-inflammatory cytokines and cells. Macrophages develop an M2 rather than an M1 phenotype. Angiogenesis and/or vasculogenesis assists either tissue regeneration or replacement with extracellular materials (fibrosis).

Fig. 2

The yin-yang of cytokines. The balance between pro-inflammatory cytokines and anti-inflammatory cytokines is critical in determining outcome. Chemokines have preferred partners that link cell trafficking to function, as indicated. Angiogenesis, tissue replacement (fibrosis) and regeneration predominantly fall within the influence of the more anti-inflammatory axis.

Fig. 3

ROS can be generated from many sources following irradiation. Released nucleotides including ATP can activate P2X purinergic receptors to open the cation pore and trigger calcium-dependent intracellular processes. This is required for activation of NADPH oxidases that can also be activated by TLR signaling to generate superoxide. Radiation damage to mitochondria is another potential source of ROS. Further DAMP and pro-inflammatory cytokines signaling, the DNA damage response through Bax, and the formation of inflammasomes can all perpetuate ROS generation by forming positive feedback circuits. Adenosine can be generated from nucleotides by ectonucleotidases such as CD39 to signal through the adenosine receptors (AR) to negatively regulate inflammation, as does the production of anti-inflammatory cytokines.

Fig. 4

Antigen-specific Th cells differentiate under the influence of cytokines into subsets with distinct cytokine profiles and functions. Two classes of Tregs (iTregs and nTregs) produce immunosuppressive effector cytokines that work by juxtacrine and paracrine action. nTregs from the thymus can be influenced by IL-6 and TGF-β to develop into auto-inflammatory Th17 cells, while blocking iTreg development. Other Treg subsets have been described, but are less well established.

Fig. 5

Within the first month, the cytokine response of C57Bl/6 mice that develop fibrosis in response to 20 Gy local thoracic irradiation is not markedly different from that of C3H/HeN mice that develop pneumonitis, as assessed by an RNase protection assay of whole lung. However, macrophage (Mac1+ve) infiltration increases with time in irradiated C3H/HeN lungs, followed by large increases in pro-inflammatory cytokines that leads to their death by pneumonitis. C57Bl/6 mice control this pro-inflammatory response, but later develop high levels of IL-6 and TGF-β that lead to lung fibrosis.