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Androgen deprivation modulates the inflammatory response induced by irradiation.

Wu CT, Chen WC, Lin PY, Liao SK, Chen MF - BMC Cancer (2009)

Bottom Line: We found androgen deprivation by castration significantly augmented RT-induced inflammation, associated with the increase NF-kappaB activation and COX-2 expression.However, administration of flutamide had no obvious effect on the radiation-induced inflammation response in the lung and intestine.When irradiation was given to patients with total androgen deprivation, the augmenting effects on the RT-induced inflammation and fibrosis should take into consideration for complications associated with radiotherapy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Urology, Chang Gung Memorial Hospital, Linko, Taiwan. chuntewu@adm.cgmh.org.tw

ABSTRACT

Background: The aim of this study was to determine whether radiation (RT)-induced inflammatory responses and organ damage might be modulated by androgen deprivation therapies.

Methods: The mRNA and tissue sections obtained from the lungs, intestines and livers of irradiated mice with or without androgen deprivation were analyzed by real-time PCR and histological analysis. Activation of NF-kappa B was examined by measuring nuclear protein levels in the intestine and lung 24 h after irradiation. We also examined the levels of cyclooxygenase-2 (COX-2), TGF-beta1 and p-AKT to elucidate the related pathway responsible to irradiation (RT) -induced fibrosis.

Results: We found androgen deprivation by castration significantly augmented RT-induced inflammation, associated with the increase NF-kappaB activation and COX-2 expression. However, administration of flutamide had no obvious effect on the radiation-induced inflammation response in the lung and intestine. These different responses were probably due to the increase of RT-induced NF-kappaB activation and COX-2 expression by castration or lupron treatment. In addition, our data suggest that TGF-beta1 and the induced epithelial-mesenchymal transition (EMT) via the PI3K/Akt signaling pathway may contribute to RT-induced fibrosis.

Conclusion: When irradiation was given to patients with total androgen deprivation, the augmenting effects on the RT-induced inflammation and fibrosis should take into consideration for complications associated with radiotherapy.

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Related in: MedlinePlus

Activation of NF-κB in murine lung and intestinal tissues. (A) The activation of NF-κB was detected by EMSA in intestinal tissues. Representative figures are shown for (a) unirradiated control mice, (b) irradiated mice 24 h after exposure to 20 Gy, (c) flutamide-treated mice 24 h after exposure to 20 Gy and (d) castrated mice 24 h after exposure to 20 Gy. These findings demonstrate that there was significant attenuation of RT-induced the binding activity of nuclear NF-κB in castrated mice, whereas androgen deprivation by flutamide did not induce NF-κB activation. (Y axis represents the relative level which is normalized by the level of NF-κB activity in control condition). (B) Expression of COX-2 protein in irradiated murine intestinal tissue with or without androgen deprivation including castration and flutamide administration. (a, control; b, irradiation; c, castration alone; d, castration plus irradiation; e, flutamide administration; f, irradiation plus flutamide administration). Triplicate experiments were performed for the analysis. (Y axis represents the relative protein level which is normalized by the protein level of COX-2 in control condition). (C) Expression of β-catenin, vimentin and p-Akt in the intestinal tissues after various treatments (a, control; b, treated with TGF-β1; c, treated with TGF-β1+ wortmannin; d, irradiated tissue 24 h after 20 Gy; e, after pretreatment with wortmannin for 12 h followed by 20 Gy irradiation). Triplicate experiments were performed for the analysis.
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Figure 5: Activation of NF-κB in murine lung and intestinal tissues. (A) The activation of NF-κB was detected by EMSA in intestinal tissues. Representative figures are shown for (a) unirradiated control mice, (b) irradiated mice 24 h after exposure to 20 Gy, (c) flutamide-treated mice 24 h after exposure to 20 Gy and (d) castrated mice 24 h after exposure to 20 Gy. These findings demonstrate that there was significant attenuation of RT-induced the binding activity of nuclear NF-κB in castrated mice, whereas androgen deprivation by flutamide did not induce NF-κB activation. (Y axis represents the relative level which is normalized by the level of NF-κB activity in control condition). (B) Expression of COX-2 protein in irradiated murine intestinal tissue with or without androgen deprivation including castration and flutamide administration. (a, control; b, irradiation; c, castration alone; d, castration plus irradiation; e, flutamide administration; f, irradiation plus flutamide administration). Triplicate experiments were performed for the analysis. (Y axis represents the relative protein level which is normalized by the protein level of COX-2 in control condition). (C) Expression of β-catenin, vimentin and p-Akt in the intestinal tissues after various treatments (a, control; b, treated with TGF-β1; c, treated with TGF-β1+ wortmannin; d, irradiated tissue 24 h after 20 Gy; e, after pretreatment with wortmannin for 12 h followed by 20 Gy irradiation). Triplicate experiments were performed for the analysis.

Mentions: NF-κB plays an important role in RT-induced inflammation [21]. To clarify whether the mechanisms responsible to the augmentation of RT-induced inflammation by castration, but not by administration of flutamide is related to the activation of NF-κB, EMSA was performed on tissues following various treatments. As shown in Figure 5A, exposure to 20 Gy promoted NF-κB binding in the lung and intestine, compared to that observed in unirradiated murine tissues. Flutamide administration appeared the tendency to attenuate the binding activity of NF-κB. However, exposure to 20 Gy in castrated mice significantly promoted NF-κB binding. We further examined the expression of COX-2 (Figure 5B), which is one of the main down-stream genes of NF-κB to induce inflammatory response.


Androgen deprivation modulates the inflammatory response induced by irradiation.

Wu CT, Chen WC, Lin PY, Liao SK, Chen MF - BMC Cancer (2009)

Activation of NF-κB in murine lung and intestinal tissues. (A) The activation of NF-κB was detected by EMSA in intestinal tissues. Representative figures are shown for (a) unirradiated control mice, (b) irradiated mice 24 h after exposure to 20 Gy, (c) flutamide-treated mice 24 h after exposure to 20 Gy and (d) castrated mice 24 h after exposure to 20 Gy. These findings demonstrate that there was significant attenuation of RT-induced the binding activity of nuclear NF-κB in castrated mice, whereas androgen deprivation by flutamide did not induce NF-κB activation. (Y axis represents the relative level which is normalized by the level of NF-κB activity in control condition). (B) Expression of COX-2 protein in irradiated murine intestinal tissue with or without androgen deprivation including castration and flutamide administration. (a, control; b, irradiation; c, castration alone; d, castration plus irradiation; e, flutamide administration; f, irradiation plus flutamide administration). Triplicate experiments were performed for the analysis. (Y axis represents the relative protein level which is normalized by the protein level of COX-2 in control condition). (C) Expression of β-catenin, vimentin and p-Akt in the intestinal tissues after various treatments (a, control; b, treated with TGF-β1; c, treated with TGF-β1+ wortmannin; d, irradiated tissue 24 h after 20 Gy; e, after pretreatment with wortmannin for 12 h followed by 20 Gy irradiation). Triplicate experiments were performed for the analysis.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 5: Activation of NF-κB in murine lung and intestinal tissues. (A) The activation of NF-κB was detected by EMSA in intestinal tissues. Representative figures are shown for (a) unirradiated control mice, (b) irradiated mice 24 h after exposure to 20 Gy, (c) flutamide-treated mice 24 h after exposure to 20 Gy and (d) castrated mice 24 h after exposure to 20 Gy. These findings demonstrate that there was significant attenuation of RT-induced the binding activity of nuclear NF-κB in castrated mice, whereas androgen deprivation by flutamide did not induce NF-κB activation. (Y axis represents the relative level which is normalized by the level of NF-κB activity in control condition). (B) Expression of COX-2 protein in irradiated murine intestinal tissue with or without androgen deprivation including castration and flutamide administration. (a, control; b, irradiation; c, castration alone; d, castration plus irradiation; e, flutamide administration; f, irradiation plus flutamide administration). Triplicate experiments were performed for the analysis. (Y axis represents the relative protein level which is normalized by the protein level of COX-2 in control condition). (C) Expression of β-catenin, vimentin and p-Akt in the intestinal tissues after various treatments (a, control; b, treated with TGF-β1; c, treated with TGF-β1+ wortmannin; d, irradiated tissue 24 h after 20 Gy; e, after pretreatment with wortmannin for 12 h followed by 20 Gy irradiation). Triplicate experiments were performed for the analysis.
Mentions: NF-κB plays an important role in RT-induced inflammation [21]. To clarify whether the mechanisms responsible to the augmentation of RT-induced inflammation by castration, but not by administration of flutamide is related to the activation of NF-κB, EMSA was performed on tissues following various treatments. As shown in Figure 5A, exposure to 20 Gy promoted NF-κB binding in the lung and intestine, compared to that observed in unirradiated murine tissues. Flutamide administration appeared the tendency to attenuate the binding activity of NF-κB. However, exposure to 20 Gy in castrated mice significantly promoted NF-κB binding. We further examined the expression of COX-2 (Figure 5B), which is one of the main down-stream genes of NF-κB to induce inflammatory response.

Bottom Line: We found androgen deprivation by castration significantly augmented RT-induced inflammation, associated with the increase NF-kappaB activation and COX-2 expression.However, administration of flutamide had no obvious effect on the radiation-induced inflammation response in the lung and intestine.When irradiation was given to patients with total androgen deprivation, the augmenting effects on the RT-induced inflammation and fibrosis should take into consideration for complications associated with radiotherapy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Urology, Chang Gung Memorial Hospital, Linko, Taiwan. chuntewu@adm.cgmh.org.tw

ABSTRACT

Background: The aim of this study was to determine whether radiation (RT)-induced inflammatory responses and organ damage might be modulated by androgen deprivation therapies.

Methods: The mRNA and tissue sections obtained from the lungs, intestines and livers of irradiated mice with or without androgen deprivation were analyzed by real-time PCR and histological analysis. Activation of NF-kappa B was examined by measuring nuclear protein levels in the intestine and lung 24 h after irradiation. We also examined the levels of cyclooxygenase-2 (COX-2), TGF-beta1 and p-AKT to elucidate the related pathway responsible to irradiation (RT) -induced fibrosis.

Results: We found androgen deprivation by castration significantly augmented RT-induced inflammation, associated with the increase NF-kappaB activation and COX-2 expression. However, administration of flutamide had no obvious effect on the radiation-induced inflammation response in the lung and intestine. These different responses were probably due to the increase of RT-induced NF-kappaB activation and COX-2 expression by castration or lupron treatment. In addition, our data suggest that TGF-beta1 and the induced epithelial-mesenchymal transition (EMT) via the PI3K/Akt signaling pathway may contribute to RT-induced fibrosis.

Conclusion: When irradiation was given to patients with total androgen deprivation, the augmenting effects on the RT-induced inflammation and fibrosis should take into consideration for complications associated with radiotherapy.

Show MeSH
Related in: MedlinePlus