Radiation Inhibits Interleukin-12 Production via Inhibition of C-Rel through the Interleukin-6/ Signal Transducer and Activator of Transcription 3 Signaling Pathway in Dendritic Cells

Abstract

Radiotherapy (RT) is a potent anti-tumor modality. However, unwanted effects including increased recurrence and metastasis that involve factors such as cytokines, which induce complex molecular mechanisms, have also been reported. In a previous study, we showed that interleukin (IL)-12 and radiotherapy combination treatment suppressed tumor growth and metastasis in a hepatoma mouse model. In this study, we investigated the mechanism underlying the IL-12 anti-tumor effect during radiotherapy. In tumor-bearing mice, irradiation decreased IL-12 expression in the tumors and spleens. However, a number of dendritic cells infiltrated into the tumors in which IL-12 expression did not decrease. To further study the underlying detailed mechanism for this decrease in IL-12, LPS-stimulated bone marrow–derived dendritic cells (BMDCs) were irradiated, and then IL-12– and IL-6–associated molecules were examined in irradiated tumors and BMDCs. Irradiation resulted in IL-12 suppression and IL-6 increase. IL-6 and signal transducer and activator of transcription 3 (STAT3) inhibitors restored the irradiation-induced IL-12 decrease via suppression of C-Rel activation. Taken together, our study suggests that irradiation-induced IL-6 can decrease IL-12 production through the inhibition of C-Rel phosphorylation by the IL-6/STAT3 signaling pathway.

Modulating Both Tumor Cell Death and Innate Immunity Is Essential for Improving Radiation Therapy Effectiveness

“…Irradiation at 30 Gy did not impact on DCs endocytic, phagocytic and migratory capacity but significantly inhibited IL-12 production by mature DCs while IL-10 production was unaffected ( 103 ). Inhibition of IL-12 expression in DCs by irradiation was in part mediated by an increase of IL-6 and activation of down stream signal transducer and activator of transcription 3, which led to inhibition of c-REL transcription factor ( 128 ). In addition, irradiated peptide-pulsed mature DCs showed impaired ability to prime naïve CTL ( 103 ).…”

Soluble interleukin-6 receptor mediated fatigue highlights immunological heterogeneity of patients with early breast cancer who undergo radiation therapy

“…Medium-strength associations suggest that the irradiation of a sufficiently large volume of liver is associated with a peripherally detectable increase in sIL-6R concentration (hepatocytes are a main source of systemic sIL-6R). 15 No correlations existed for left-sided tumors, which supports the hypothesis that radiation dose to the liver was a substantive effect rather than a consequence of increased BMI. However, a higher BMI was clearly associated with both larger volumes of hepatic irradiation (for right-sided disease) and elevated peripheral sIL-6R.…”

How Macrophages Become Transcriptionally Dysregulated: A Hidden Impact of Antitumor Therapy

“…The generalized effect of X-ray and 𝛾-photon radiotherapy is STAT3 activation, which is observed in TAMs in response to all clinical doses of radiation. Irradiation promotes IL-6 production by the tumor microenvironment, which results in STAT3 phosphorylation and subsequent anti-inflammatory CCL2, CCL4, VEGF, and TGF-β cytokine production [ 149 , 158 , 160 , 189 ]. It is worth noting that STAT3 signaling also promotes cell survival after irradiation exposure via induction of anti-apoptotic proteins (survivin and Bcl-2), and this effect is more profound for M2-like TAMs [ 158 , 160 , 190 ].…”