Follistatin is a potent regulator of the inflammatory response and binds to and inhibits
activin A action.
Activin A is a member of the TGFβ
protein superfamily which has regulatory roles in the inflammatory response and in the fibrotic process.
Fibrosis can occur following cell injury and cell death induced by agents such as ionizing radiation (IR). IR is used to treat
cancer and marked fibrotic response is a normal tissue (non-tumour) consequence in a fraction of patients under the current dose regimes. The discovery and development of a therapeutic to abate
fibrosis in these radiosensitive patients would be a major advance for
cancer radiotherapy. Likewise, prediction of which patients are susceptible to
fibrosis would enable individualization of treatment and provide an opportunity for pre-emptive
fibrosis control and better tumour treatment outcomes. The levels of
activin A and
follistatin were measured in fibroblasts derived from patients who developed severe
radiation-induced fibrosis following
radiotherapy and compared to fibroblasts from patients who did not. Both
follistatin and
activin A gene expression levels were increased following IR and the
follistatin gene expression level was lower in the fibroblasts from
fibrosis patients compared to controls at both basal levels and after IR. The major
follistatin transcript variants were found to have a similar response to IR and both were reduced in
fibrosis patients. Levels of
follistatin and
activin A secreted in the fibroblast culture medium also increased in response to IR and the relative
follistatin protein levels were significantly lower in the samples derived from
fibrosis patients. The decrease in the
follistatin levels can lead to an increased bioactivity of
activin A and hence may provide a useful measurement to identify patients at risk of a severe fibrotic response to IR. Additionally,
follistatin, by its ability to neutralise the actions of
activin A may be of value as an anti-fibrotic for
radiation induced fibrosis.