Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice.
Polymorphisms of interleukin-1beta (IL-1beta) are associated with an increased risk of solid malignancies. Here, we show that stomach-specific expression of human IL-1beta in transgenic mice leads to spontaneous gastric inflammation and cancer that correlate with early recruitment of myeloid-derived suppressor cells (MDSCs) to the stomach. IL-1beta activates MDSCs in vitro and in vivo through an IL-1RI/NF-kappaB pathway. IL-1beta transgenic mice deficient in T and B lymphocytes develop gastric dysplasia accompanied by a marked increase in MDSCs in the stomach. Antagonism of IL-1 receptor signaling inhibits the development of gastric preneoplasia and suppresses MDSC mobilization. These results demonstrate that pathologic elevation of a single proinflammatory cytokine may be sufficient to induce neoplasia and provide a direct link between IL-1beta, MDSCs, and carcinogenesis.
Tu
Shuiping
S
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Bhagat
Govind
G
Cui
Guanglin
G
Takaishi
Shigeo
S
Kurt-Jones
Evelyn A
EA
Rickman
Barry
B
Betz
Kelly S
KS
Penz-Oesterreicher
Melitta
M
Bjorkdahl
Olle
O
Fox
James G
JG
Wang
Timothy C
TC
D000818:Animals; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005756:Gastritis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D017506:H(+)-K(+)-Exchanging ATPase / Q000502:physiology; D016481:Helicobacter Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D044922:Helicobacter felis / Q000472:pathogenicity; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism*; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D022423:Myeloid Cells / Q000276:immunology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011230:Precancerous Conditions / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D014162:Transfection
D004268:DNA-Binding Proteins; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D016328:NF-kappa B; D012333:RNA, Messenger; C499308:Rag2 protein, mouse; D017472:Receptors, Interleukin-1; D017506:H(+)-K(+)-Exchanging ATPase