title: Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist.
abstract: Vertebrate Toll-like receptor 5 (TLR5) recognizes bacterial flagellin proteins and activates innate immune responses to motile bacteria. In addition, activation of TLR5 signaling can inhibit growth of TLR5-expressing tumors and protect normal tissues from radiation and ischemia-reperfusion injuries. To understand the mechanisms behind these phenomena at the organismal level, we assessed nuclear factor kappa B (NF-κB) activation (indicative of TLR5 signaling) in tissues and cells of mice treated with CBLB502, a pharmacologically optimized flagellin derivative. This identified the liver and gastrointestinal tract as primary CBLB502 target organs. In particular, liver hepatocytes were the main cell type directly and specifically responding to systemic administration of CBLB502 but not to that of the TLR4 agonist LPS. To assess CBLB502 impact on other pathways, we created multireporter mice with hepatocytes transduced in vivo with reporters for 46 inducible transcription factor families and found that along with NF-κB, CBLB502 strongly activated STAT3-, phenobarbital-responsive enhancer module (PREM), and activator protein 1 (AP-1-) -driven pathways. Livers of CBLB502-treated mice displayed induction of numerous immunomodulatory factors and massive recruitment of various types of immune cells. This led to inhibition of growth of liver metastases of multiple tumors regardless of their TLR5 status. The changed liver microenvironment was not, however, hepatotoxic, because CBLB502 induced resistance to Fas-mediated apoptosis in normal liver cells. Temporary occlusion of liver blood circulation prevented CBLB502 from protecting hematopoietic progenitors in lethally irradiated mice, indicating involvement of a factor secreted by responding liver cells. These results define the liver as the key mediator of TLR5-dependent effects in vivo and suggest clinical applications for TLR5 agonists as hepatoprotective and antimetastatic agents.
authors: Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors: Lyudmila G
authors: LG
authors: Burdelya
authors: Craig M
authors: CM
authors: Brackett
authors: Bojidar
authors: B
authors: Kojouharov
authors: Ilya I
authors: II
authors: Gitlin
authors: Katerina I
authors: KI
authors: Leonova
authors: Anatoli S
authors: AS
authors: Gleiberman
authors: Semra
authors: S
authors: Aygun-Sunar
authors: Jean
authors: J
authors: Veith
authors: Christopher
authors: C
authors: Johnson
authors: Gary J
authors: GJ
authors: Haderski
authors: Patricia
authors: P
authors: Stanhope-Baker
authors: Shyam
authors: S
authors: Allamaneni
authors: Joseph
authors: J
authors: Skitzki
authors: Ming
authors: M
authors: Zeng
authors: Elena
authors: E
authors: Martsen
authors: Alexander
authors: A
authors: Medvedev
authors: Dmitry
authors: D
authors: Scheblyakov
authors: Nataliya M
authors: NM
authors: Artemicheva
authors: Denis Y
authors: DY
authors: Logunov
authors: Alexander L
authors: AL
authors: Gintsburg
authors: Boris S
authors: BS
authors: Naroditsky
authors: Sergei S
authors: SS
authors: Makarov
authors: Andrei V
authors: AV
authors: Gudkov
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009368:Neoplasm Transplantation; D009504:Neutrophils / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D011837:Radiation-Protective Agents / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D051198:Toll-Like Receptor 5 / Q000819:agonists*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; C528306:CBLB502; D016328:NF-kappa B; D010455:Peptides; D011837:Radiation-Protective Agents; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051198:Toll-Like Receptor 5; D019014:fas Receptor
keywords: Salmonella; breast cancer; colon cancer; natural killer cells; neutrophils
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