Irradiation Induces Regionally Specific Alterations in Pro-inflammatory Environments in Rat Brain

Overview

Journal Int J Radiat Biol

Specialty Radiology

Date 2010 Feb 13

PMID 20148699

Citations 80

Authors

Won Hee Lee

William E Sonntag

Matthew Mitschelen

Han Yan

Yong Woo Lee

Affiliations

Soon will be listed here.

Abstract

Purpose: Pro-inflammatory environments in the brain have been implicated in the onset and progression of neurological disorders. In the present study, we investigate the hypothesis that brain irradiation induces regionally specific alterations in cytokine gene and protein expression.

Materials And Methods: Four month old F344 x BN rats received either whole brain irradiation with a single dose of 10 Gy gamma-rays or sham-irradiation, and were maintained for 4, 8, and 24 h following irradiation. The mRNA and protein expression levels of pro-inflammatory mediators were analysed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining. To elucidate the molecular mechanisms of irradiation-induced brain inflammation, effects of irradiation on the DNA-binding activity of pro-inflammatory transcription factors were also examined.

Results: A significant and marked up-regulation of mRNA and protein expression of pro-inflammatory mediators, including tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and monocyte chemoattractant protein-1 (MCP-1), was observed in hippocampal and cortical regions isolated from irradiated brain. Cytokine expression was regionally specific since TNF-alpha levels were significantly elevated in cortex compared to hippocampus (57% greater) and IL-1beta levels were elevated in hippocampus compared to cortical samples (126% greater). Increases in cytokine levels also were observed after irradiation of mouse BV-2 microglial cells. A series of electrophoretic mobility shift assays (EMSA) demonstrated that irradiation significantly increased activation of activator protein-1 (AP-1), nuclear factor-kappaB (NF-kappaB), and cAMP response element-binding protein (CREB).

Conclusion: The present study demonstrated that whole brain irradiation induces regionally specific pro-inflammatory environments through activation of AP-1, NF-kappaB, and CREB and overexpression of TNF-alpha, IL-1beta, and MCP-1 in rat brain and may contribute to unique pathways for the radiation-induced impairments in tissue function.

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References

Lee Y, Hirani A, Kyprianou N, Toborek M . Human immunodeficiency virus-1 Tat protein up-regulates interleukin-6 and interleukin-8 expression in human breast cancer cells. Inflamm Res. 2005; 54(9):380-9. DOI: 10.1007/s00011-005-1371-8. View

Hong J, Chiang C, Campbell I, Sun J, Withers H, McBride W . Induction of acute phase gene expression by brain irradiation. Int J Radiat Oncol Biol Phys. 1995; 33(3):619-26. DOI: 10.1016/0360-3016(95)00279-8. View

Park J, Qiao L, Su Z, Hinman D, Willoughby K, McKinstry R . Ionizing radiation modulates vascular endothelial growth factor (VEGF) expression through multiple mitogen activated protein kinase dependent pathways. Oncogene. 2001; 20(25):3266-80. DOI: 10.1038/sj.onc.1204258. View

Bradford M . A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976; 72:248-54. DOI: 10.1016/0003-2697(76)90527-3. View

Chiang C, Hong J, Stalder A, Sun J, Withers H, McBride W . Delayed molecular responses to brain irradiation. Int J Radiat Biol. 1997; 72(1):45-53. DOI: 10.1080/095530097143527. View

Iwata E, Asanuma M, Nishibayashi S, Kondo Y, Ogawa N . Different effects of oxidative stress on activation of transcription factors in primary cultured rat neuronal and glial cells. Brain Res Mol Brain Res. 1997; 50(1-2):213-20. DOI: 10.1016/s0169-328x(97)00190-3. View

Gaugler M, Squiban C, Van der Meeren A, Bertho J, Vandamme M, Mouthon M . Late and persistent up-regulation of intercellular adhesion molecule-1 (ICAM-1) expression by ionizing radiation in human endothelial cells in vitro. Int J Radiat Biol. 1997; 72(2):201-9. DOI: 10.1080/095530097143428. View

Linard C, Marquette C, Mathieu J, Pennequin A, Clarencon D, Mathe D . Acute induction of inflammatory cytokine expression after gamma-irradiation in the rat: effect of an NF-kappaB inhibitor. Int J Radiat Oncol Biol Phys. 2004; 58(2):427-34. DOI: 10.1016/j.ijrobp.2003.09.039. View

Linard C, Ropenga A, Vozenin-Brotons M, Chapel A, Mathe D . Abdominal irradiation increases inflammatory cytokine expression and activates NF-kappaB in rat ileal muscularis layer. Am J Physiol Gastrointest Liver Physiol. 2003; 285(3):G556-65. DOI: 10.1152/ajpgi.00094.2003. View

10.

Voges J, Treuer H, Sturm V, Buchner C, Lehrke R, Kocher M . Risk analysis of linear accelerator radiosurgery. Int J Radiat Oncol Biol Phys. 1996; 36(5):1055-63. DOI: 10.1016/s0360-3016(96)00422-1. View

11.

Mori K, Tani M, Kamata K, Kawamura H, Urata Y, Goto S . Mitogen-activated protein kinase, ERK1/2, is essential for the induction of vascular endothelial growth factor by ionizing radiation mediated by activator protein-1 in human glioblastoma cells. Free Radic Res. 2000; 33(2):157-66. DOI: 10.1080/10715760000300711. View

12.

CALVO W, Hopewell J, Reinhold H, Yeung T . Time- and dose-related changes in the white matter of the rat brain after single doses of X rays. Br J Radiol. 1988; 61(731):1043-52. DOI: 10.1259/0007-1285-61-731-1043. View

13.

SHELINE G, Wara W, Smith V . Therapeutic irradiation and brain injury. Int J Radiat Oncol Biol Phys. 1980; 6(9):1215-28. DOI: 10.1016/0360-3016(80)90175-3. View

14.

Haveman J, Geerdink A, Rodermond H . TNF, IL-1 and IL-6 in circulating blood after total-body and localized irradiation in rats. Oncol Rep. 1998; 5(3):679-83. DOI: 10.3892/or.5.3.679. View

15.

Zhou D, Yu T, Chen G, Brown S, Yu Z, Mattson M . Effects of NF-kappaB1 (p50) targeted gene disruption on ionizing radiation-induced NF-kappaB activation and TNFalpha, IL-1alpha, IL-1beta and IL-6 mRNA expression in vivo. Int J Radiat Biol. 2001; 77(7):763-72. DOI: 10.1080/09553000110050047. View

16.

Molla M, Panes J . Radiation-induced intestinal inflammation. World J Gastroenterol. 2007; 13(22):3043-6. PMC: 4172609. DOI: 10.3748/wjg.v13.i22.3043. View

17.

Lee Y, Eum S, Nath A, Toborek M . Estrogen-mediated protection against HIV Tat protein-induced inflammatory pathways in human vascular endothelial cells. Cardiovasc Res. 2004; 63(1):139-48. DOI: 10.1016/j.cardiores.2004.03.006. View

18.

Johnston C, Williams J, Okunieff P, Finkelstein J . Radiation-induced pulmonary fibrosis: examination of chemokine and chemokine receptor families. Radiat Res. 2002; 157(3):256-65. DOI: 10.1667/0033-7587(2002)157[0256:ripfeo]2.0.co;2. View

19.

Han S, Song J, Yun Y, Yi S . Effect of gamma radiation on cytokine expression and cytokine-receptor mediated STAT activation. Int J Radiat Biol. 2006; 82(9):686-97. DOI: 10.1080/09553000600930699. View

20.

Brach M, Hass R, Sherman M, Gunji H, Weichselbaum R, Kufe D . Ionizing radiation induces expression and binding activity of the nuclear factor kappa B. J Clin Invest. 1991; 88(2):691-5. PMC: 295415. DOI: 10.1172/JCI115354. View