title: IL-1RT1 signaling antagonizes IL-11 induced STAT3 dependent cardiac and antral stomach tumor development through myeloid cell enrichment.
abstract: IL-1 is key driver of gastric tumorigenesis and is a downstream target of IL-11 signaling. Recently, IL-1 cytokines, particularly IL-1β, have been flagged as therapeutic targets for gastric cancer treatment. Here, we assess the requirement for IL-1 signaling in gastric tumorigenesis. gp130757FF xIL-1RT1-/- mice were generated to determine the pathological consequence of ablated IL-1 signaling in the IL-11 dependent gp130757FF mouse model of gastric tumorigenesis. Gastric lesions in gp130757FF xIL-1RT1-/- mice were increased in incidence and size compared to gp130757FF mice. Proximal gastric lesions originated from the cardiac region and were associated with elevated STAT3 activation, loss of specialized gastric cells and a modulated immune response including increased expression of TNF-α and MDSC associated genes. Administration of IL-11 to IL-1RT1-/- mice showed similar changes to gp130757FF xIL-1RT1-/- mice. Spleens from IL-11 treated wildtype mice showed an enrichment of MDSC and gp130757FF xIL-1RT1-/- mice had increased MDSCs in the stomach compared to gp130757FF mice. Furthermore, crossing TNF-α-/- to gp130757FF mice resulted in reduced lesion size. We conclude that IL-1 signaling antagonizes IL-11/STAT3 mediated pathology and the genetic deletion of IL-1RT1 results in increased tumor burden. We provide evidence that a likely mechanism is due to IL-11/STAT3 dependent enrichment of MDSCs.
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, 3052 Australia.|Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria, 3052 Australia.
authors.forename: Jon N
authors.initials: JN
authors.lastname: Buzzelli
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, 3052 Australia.
authors.forename: Dan I
authors.initials: DI
authors.lastname: Pavlic
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, 3052 Australia.
authors.forename: Heather V
authors.initials: HV
authors.lastname: Chalinor
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, 3052 Australia.
authors.forename: Louise
authors.initials: L
authors.lastname: O'Connor
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, 3052 Australia.|Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria, 3052 Australia.
authors.forename: Trevelyan R
authors.initials: TR
authors.lastname: Menheniott
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, 3052 Australia.|Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria, 3052 Australia.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Giraud
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, 3052 Australia.Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria, 3052 Australia.|Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, 3052 Australia.Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria, 3052 Australia.
authors.forename: Louise M
authors.initials: LM
authors.lastname: Judd
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006338:Heart Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D017370:Interleukin-11 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D023461:Myeloid Progenitor Cells / Q000378:metabolism* / Q000473:pathology; D053573:Receptors, Interleukin-1 Type I / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: C583355:IL1R1 protein, mouse; D017370:Interleukin-11; D053573:Receptors, Interleukin-1 Type I; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse