All-transretinoic acid modulates radiation-induced proliferation of lung fibroblasts via IL-6/IL-6R system

Abstract

Although high-dose thoracic radiotherapy is an effective strategy for some malignancies including lung cancers and malignant lymphomas, it often causes complications of radiation fibrosis. To study the mechanism initiating tissue fibrosis, we investigated irradiation-induced cytokine production from human lung fibroblastic cells and found that IL-6 production was stimulated by irradiation. IL-6 is an autocrine growth factor for human myeloma cells, and retinoic acid is reported to inhibit their growth. Thus we evaluated the effect of all- trans retinoic acid (ATRA) on cell proliferation of lung fibroblasts along with the cytokine/receptor system. Irradiation-dependent stimulation of IL-6 production was correlated with increased NF-κB activity, and ATRA reduced this effect. Irradiation also increased the levels of mRNA for IL-6R and gp130, which were blocked by coexisting ATRA. Furthermore, IL-6 stimulated cell proliferation in dose-dependent manner but was overcome by pharmacological concentration of ATRA. These effects of ATRA were inhibited by rottlerin, which suggests ATRA abolished irradiation-induced stimulation through a PKCδ-dependent pathway. Finally, we demonstrated that IL-6 transcripts in the lung were upregulated at 2 mo after irradiation, and the effect was inhibited by the intraperitoneal administration of ATRA. ATRA is expected to have an advantage for radiotherapy in its antitumor effects, as reported previously, and to prevent radiotherapy-induced pulmonary injury.

All-trans retinoic acid induces proliferation of an irradiated stem cell supporting stromal cell line AFT024

“…We demonstrated that ATRA induced proliferation of irradiated AFT024 cells as shown by immunohistochemistry, cell cycle analysis, and gene expression studies. Previous studies in fetal rat hepatocytes and HepG2 cell lines [11], as well as in irradiated acute promyelocytic leukemia cell-line HL-60 [12] and human lung fibroblast cells [13], have demonstrated the antiproliferative and differentiating effects of ATRA. To our knowledge, this is the first report that ATRA may induce proliferation of irradiated stromal cells.…”

Role of Interleukin-1 in Radiation-Induced Cardiomyopathy

“…XRT activates inflammatory pathways in several cell types, including endothelial cells, macrophages and fibroblasts, that potentially participate in the initiation and amplification of cardiac toxicity (7)(8)(9)(10). Interleukin (IL)-1 is the prototypical inflammatory cytokine activated in response to tissue injury (11)(12)(13) and has been found to be increased in the heart Thoracic X-ray therapy (XRT), used in cancer treatment, is associated with increased risk of heart failure.…”

Microchamber arrays for the identification of individual cells exposed to an X-ray microbeam

“…In post-irradiation analysis, immunofluorescence stainings were performed to detect the production of IL-6 and c-H2AX [17,18]. As mentioned before, the autocrine induction of IL-6 in PC12 under ionizing radiation was reported.…”