Activation of Nuclear Factor κB In vivo Selectively Protects the Murine Small Intestine against Ionizing Radiation-Induced Damage

Exposure of mice to total body irradiation induces nuclear factor κB (NFκB) activation in a tissue-specific manner. In addition to the spleen, lymph nodes, and bone marrow, the tissues that exhibit NFκB activation now include the newly identified site of the intestinal epithelial cells. NFκB activated by total body irradiation mainly consists of NFκB p50/RelA heterodimers, and genetically targeted disruption of the NFκB p50 gene in mice significantly decreased the activation. By comparing tissue damage and lethality in wild-type and NFκB p50 knockout (p50−/−) mice after they were exposed to increasing doses of total body irradiation, we additionally examined the role of NFκB activation in total body irradiation-induced tissue damage. The results show that p50−/− mice are more sensitive to total body irradiation-induced lethality than wild-type mice (LD50/Day 7: wild-type = 13.12 Gy versus p50−/− = 7.75 Gy and LD50/Day 30: wild-type = 9.31 Gy versus p50−/− = 7.81 Gy). The increased radiosensitivity of p50−/− mice was associated with an elevated level of apoptosis in intestinal epithelial cells and decreased survival of the small intestinal crypts compared with wild-type mice (P < 0.01). In addition, RelA/TNFR1-deficient (RelA/TNFR1−/−) mice also exhibited a significant increase in intestinal epithelial cell apoptosis after they were exposed to total body irradiation as compared with TNFR1-deficient (TNFR1−/−) mice (P < 0.01). In contrast, no significant increase in total body irradiation-induced apoptosis or tissue injury was observed in bone marrow cells, spleen lymphocytes, and the liver, heart, lung, and kidney of p50−/− mice in comparison with wild-type mice. These findings indicate that activation of NFκB selectively protects the small intestine against ionizing radiation-induced damage.

[1]  M. Karin,et al.  IκB-kinaseβ-dependent NF-κB activation provides radioprotection to the intestinal epithelium , 2004 .

[2]  M. Karin,et al.  IkappaB-kinasebeta-dependent NF-kappaB activation provides radioprotection to the intestinal epithelium. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Daohong Zhou,et al.  Ionizing radiation and busulfan inhibit murine bone marrow cell hematopoietic function via apoptosis-dependent and -independent mechanisms. , 2003, Experimental hematology.

[4]  Daohong Zhou,et al.  Cellular origin of ionizing radiation‐induced NF‐κB activation in vivo and role of NF‐κB in ionizing radiation‐induced lymphocyte apoptosis , 2003 .

[5]  M. Baumann,et al.  Sustained elevation of NF‐κB DNA binding activity in radiation‐induced lung damage in rats , 2003, International journal of radiation biology.

[6]  E. Wright,et al.  Tissue‐specific p53 responses to ionizing radiation and their genetic modification: the key to tissue‐specific tumour susceptibility? , 2003, The Journal of pathology.

[7]  Daohong Zhou,et al.  Ionizing radiation and busulfan induce premature senescence in murine bone marrow hematopoietic cells. , 2003, Cancer research.

[8]  Michael Karin,et al.  NF-κB in cancer: a marked target , 2003 .

[9]  A. Meng,et al.  Cellular origin of ionizing radiation-induced NF-kappaB activation in vivo and role of NF-kappaB in ionizing radiation-induced lymphocyte apoptosis. , 2003, International journal of radiation biology.

[10]  Michael Karin,et al.  NF-kappaB in cancer: a marked target. , 2003, Seminars in cancer biology.

[11]  W. El-Deiry,et al.  Tissue-specific induction of p53 targets in vivo. , 2002, Cancer research.

[12]  R. Orlowski,et al.  NF-?B as a therapeutic target in cancer , 2002 .

[13]  R. Orlowski,et al.  NF-kappaB as a therapeutic target in cancer. , 2002, Trends in molecular medicine.

[14]  M. Jung,et al.  NF-κB signaling pathway as a target for human tumor radiosensitization , 2001 .

[15]  C. Potten,et al.  Caspase activation during spontaneous and radiation‐induced apoptosis in the murine intestine , 2001, The Journal of pathology.

[16]  A. Baldwin.  Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. , 2001, The Journal of clinical investigation.

[17]  M. Mattson,et al.  Effects of NF-κB1 (p50) targeted gene disruption on ionizing radiation-induced NF-κB activation and TNFα, IL-1α, IL-1β and IL-6 mRNA expression in vivo , 2001 .

[18]  G. Courtois,et al.  ATM Is Required for IκB Kinase (IKK) Activation in Response to DNA Double Strand Breaks* , 2000, The Journal of Biological Chemistry.

[19]  M. Jung,et al.  NF-kappa B signaling pathway as a target for human tumor radiosensitization. , 2001, Seminars in radiation oncology.

[20]  M. Mattson,et al.  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. , 2001, International journal of radiation biology.

[21]  C. Houchen,et al.  Disruption of cyclooxygenase-1 gene results in an impaired response to radiation injury. , 2000, American journal of physiology. Gastrointestinal and liver physiology.

[22]  B. Aggarwal.  Apoptosis and nuclear factor-κb: a tale of association and dissociation , 2000 .

[23]  M. Merville,et al.  Nuclear factor-kappa B, cancer, and apoptosis. , 2000, Biochemical pharmacology.

[24]  N. Perkins.  The Rel/NF-κB family: friend and foe , 2000 .

[25]  B. Dontje,et al.  Distinct functional properties of highly purified hematopoietic stem cells from mouse strains differing in stem cell numbers. , 2000, Blood.

[26]  X. Sun,et al.  p300/CBP-dependent and -independent transcriptional interference between NF-kappaB RelA and p53. , 2000, Biochemical and biophysical research communications.

[27]  M. Mayo,et al.  The transcription factor NF-kappaB: control of oncogenesis and cancer therapy resistance. , 2000, Biochimica et biophysica acta.

[28]  D. Granger,et al.  Rapid activation of NF-kappaB and AP-1 and target gene expression in postischemic rat intestine. , 2000, Gastroenterology.

[29]  E. May,et al.  Tissue and cell-specific expression of the p53-target genes: bax, fas, mdm2 and waf1/p21, before and following ionising irradiation in mice , 2000, Oncogene.

[30]  D. Boothman,et al.  Coordinate modulation of Sp1, NF‐kappa B, and p53 in confluent human malignant melanoma cells after ionizing radiation , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[31]  B. Aggarwal.  Apoptosis and nuclear factor-kappa B: a tale of association and dissociation. , 2000, Biochemical pharmacology.

[32]  N. Perkins.  The Rel/NF-kappa B family: friend and foe. , 2000, Trends in biochemical sciences.

[33]  S. Barve,et al.  A high dose of ionizing radiation induces tissue-specific activation of nuclear factor-kappaB in vivo. , 1999, Radiation research.

[34]  N. Perkins,et al.  Transcriptional Cross Talk between NF-κB and p53 , 1999, Molecular and Cellular Biology.

[35]  T. Gilmore,et al.  Control of apoptosis by Rel/NF-kappaB transcription factors. , 1999, Oncogene.

[36]  N. Perkins,et al.  Transcriptional cross talk between NF-kappaB and p53. , 1999, Molecular and cellular biology.

[37]  W. El-Deiry,et al.  p53-mediated repression of nuclear factor-kappaB RelA via the transcriptional integrator p300. , 1998, Cancer research.

[38]  Mira Jung,et al.  A novel ionizing radiation-induced signaling pathway that activates the transcription factor NF-κB , 1998, Oncogene.

[39]  M J May,et al.  NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. , 1998, Annual review of immunology.

[40]  P. Tofilon,et al.  IkappaBalpha degradation is not a requirement for the X-ray-induced activation of nuclear factor kappaB in normal rat astrocytes and human brain tumour cells. , 1998, International journal of radiation biology.

[41]  C. Potten,et al.  Apoptosis in small intestinal epithelia from p53-null mice: evidence for a delayed, p53-indepdendent G2/M-associated cell death after γ-irradiation , 1997, Oncogene.

[42]  Vijay R Baichwal,et al.  Apoptosis: Activate NF-κB or die? , 1997, Current Biology.

[43]  V R Baichwal,et al.  Activate NF-kappa B or die? , 1997, Current biology : CB.

[44]  A. Baldwin,et al.  THE NF-κB AND IκB PROTEINS: New Discoveries and Insights , 1996 .

[45]  A. Baldwin,et al.  The NF-kappa B and I kappa B proteins: new discoveries and insights. , 1996, Annual review of immunology.

[46]  D. Hallahan,et al.  E-selectin gene induction by ionizing radiation is independent of cytokine induction. , 1995, Biochemical and biophysical research communications.

[47]  K. Valerie,et al.  Ionizing radiation activates nuclear factor kappa B but fails to produce an increase in human immunodeficiency virus gene expression in stably transfected human cells. , 1995, Biochemistry.

[48]  M. Meltz,et al.  Induction of nuclear factor kappa B after low-dose ionizing radiation involves a reactive oxygen intermediate signaling pathway. , 1994, Radiation research.

[49]  D. Hallahan,et al.  Radiation induction of immediate early genes: effectors of the radiation-stress response. , 1994, International journal of radiation oncology, biology, physics.

[50]  M. Meltz,et al.  Activation of Nuclear Factor κB in Human Lymphoblastoid Cells by Low-Dose Ionizing Radiation , 1994 .

[51]  P. Baeuerle,et al.  Function and activation of NF-kappa B in the immune system. , 1994, Annual review of immunology.

[52]  M. Meltz,et al.  Activation of nuclear factor kappa B in human lymphoblastoid cells by low-dose ionizing radiation. , 1994, Radiation research.

[53]  C. Potten,et al.  Characterization of radiation-induced apoptosis in the small intestine and its biological implications. , 1994, International journal of radiation biology.

[54]  J. Norton,et al.  Early response gene signalling cascades activated by ionising radiation in primary human B cells. , 1993, Oncogene.

[55]  J. M. Lee,et al.  p53 mutations increase resistance to ionizing radiation. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[56]  T. Hirano,et al.  Ionizing radiation induces expression of interleukin 6 by human fibroblasts involving activation of nuclear factor-kappa B. , 1993, The Journal of biological chemistry.

[57]  G. Schieven,et al.  Tyrosine phosphorylation is a mandatory proximal step in radiation-induced activation of the protein kinase C signaling pathway in human B-lymphocyte precursors , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[58]  R. Weichselbaum,et al.  Ionizing radiation induces expression and binding activity of the nuclear factor kappa B. , 1991, The Journal of clinical investigation.

[59]  Der,et al.  An in vitro limiting-dilution assay of long-term repopulating hematopoietic stem cells in the mouse. , 1989, Blood.