title: Flagellin administration protects gut mucosal tissue from irradiation-induced apoptosis via MKP-7 activity.
abstract: OBJECTIVE
  Radiotherapy for neoplastic disease is associated with significant adverse enteric effects associated with excessive cell death. Ionising radiation induces cell death by a mechanism that is dependent on JNK (c-jun N-terminal kinase) pathway signalling. Additionally, it is known that cells exposed to extracellular bacterial products such as flagellin, pleiotropically activate a number of innate immune pathways, including that of JNK. The JNK pathway controls its own activity by inducing the transcription of mitogen-activated protein kinase phosphatase-7 (MKP-7) which directly targets phosphorylated JNK, thus functioning as a negative feedback loop. Previously, it has been shown that flagellin limits ionising radiation-induced mortality in mice, but the cellular mechanism of protection remained unknown.
  
  
  METHODS
  Wild-type C57BL/6 or tlr5(-/-) C57BL/6 were injected with flagellin 2 h before exposure to irradiation, and their intestines were examined for apoptosis. Candidate proteins mediating cytoprotection from irradiation were identified by expression profiling. One of these candidates, MKP-7, was cloned and packaged into adenovirus particles, used to infect cultured cells, and examined for the extent to which its activity reduced cellular apoptosis by flow cytometry or immunoblot analysis.
  
  
  RESULTS
  Flagellin pretreatment protected mice from radiation-induced intestinal mucosal injury and apoptosis via a Toll-like receptor 5 (TLR5)-dependent mechanism. Expression profiling of flagellin-treated mice showed upregulation of MKP-7, an inducible repressor of the JNK pathway. MKP-7 expression reached a maximum at 2 h after flagellin treatment, coinciding with suppression of phosphorylated JNK and JNK pathway inhibition. Furthermore, constitutive MKP-7 expression protected cultured cells from radiation-induced apoptosis.
  
  
  CONCLUSIONS
  Flagellin is a promising adjuvant for suppressing ionising radiation-induced injury. MKP-7 activity exhibits cytoprotective effects, and is thus a candidate cellular molecule for limiting the damaging effect of radiotherapy on the gastreointestinal system.
authors.affiliation: Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Rheinallt M
authors.initials: RM
authors.lastname: Jones
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Sloane
authors.forename: Huixia
authors.initials: H
authors.lastname: Wu
authors.forename: Liping
authors.initials: L
authors.lastname: Luo
authors.forename: Amrita
authors.initials: A
authors.lastname: Kumar
authors.forename: Matam Vijay
authors.initials: MV
authors.lastname: Kumar
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Gewirtz
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Neish
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D051033:Apoptosis Inducing Factor / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D019610:Cytoprotection / Q000235:genetics; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005408:Flagellin / Q000494:pharmacology / Q000627:therapeutic use*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000528:radiation effects*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D012333:RNA, Messenger / Q000235:genetics; D011833:Radiation Injuries, Experimental / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051198:Toll-Like Receptor 5 / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051033:Apoptosis Inducing Factor; D012333:RNA, Messenger; D011837:Radiation-Protective Agents; D051198:Toll-Like Receptor 5; D005408:Flagellin; D048054:Mitogen-Activated Protein Kinase 7; D048670:MAP Kinase Kinase 4