R8.2: Cytokines and the Radiation Response


Cytokines are signalling molecules that facilitate cellular communication. There are many, many cytokines that impact on most cell types, but are of particular importance in immune reactions.

Cytokines in Radiation

Cytokines are released by many cells following radiation exposure, including endothelial cells, fibroblasts, immune cells and parenchymal cells. The interplay of these cytokines is thought to be responsible for the pathogenesis of many of the effects seen following radiation exposure. The other major effect of radiation is cell death, discussed elsewhere.
Radiation released cytokines fall into several categories:

  • Cytokines that attract immune cells: These chemokines cause immune cells to enter the tissue through several methods, including attractiong of the cells and increasing the gaps between endothelial cells. Examples include interleukin 1α and interleukin 6. Inflammatory cells cause numerous other changes to occur, such as cell death, promotion of fibrosis and swelling of the tissue. These cytokines are involved in both early and late reactions - for example, the erythema seen after skin treatment is due to inflammatory cytokines.
  • Cytokines that cause fibroblast differentiation and collagen production (TGFβ, PDGF): These cytokines cause fibroblasts to differentiate into fibrocytes, which actively produce collagen proteins. This leads to scarring of the tissue and is usually observed as a late effect. The cytokines which initiate this process are often released at the time of radiation.
  • Cytokines which cause cell death. The archetypal cytokine is Tumour Necrosis Factor α, although other death inducing proteins exist. These cytokines bind to cellular death receptors and promote apoptosis by releasing caspase 8. Cell death leads to activation of other cytokines and attracts immune cells.

Example: Cytokine Release Following Lung Radiation

Reference: Rubin et al (1995) A perpetual cascade of cytokines postirradiation leads to pulmonary fibrosis, here.

Elevated expression of cytokines has been shown to occur within days of radiation exposure. Important suspects in the development of fibrosis of the lung are:

  • Interleukin 1α (IL1α): This pro-inflammatory cytokine stimulates fibroblast differentiation into fibrocytes, increases collagen production, attracts immune cells (neutrophils, macrophages) and stimulates the haematopoietic system. It is released in two peaks following radiation exposure of lung tissue. The first peak occurs in the weeks following exposure, followed by reduced production between 8 - 16 weeks. IL1α production increases after several months, correlating with pathological signs of lung fibrosis.
  • Transforming Growth Factor β (TGFβ), Platelet Derived Growth Factor (PDGF): These two cytokines are potent stimulators of fibrosis. Both show increased expression shortly after radiation exposure, increasing the production of collagen from fibroblasts.