Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Bone Marrow / immunology
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Bone Marrow / metabolism
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Bone Marrow / pathology
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Cells, Cultured
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DNA-Binding Proteins / physiology
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Enzyme-Linked Immunosorbent Assay
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Female
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Flow Cytometry
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Fluorescent Antibody Technique
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Gastritis / etiology*
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Gastritis / metabolism
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Gastritis / pathology
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H(+)-K(+)-Exchanging ATPase / physiology
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Helicobacter Infections / immunology
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Helicobacter Infections / metabolism
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Helicobacter Infections / virology
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Helicobacter felis / pathogenicity
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Inflammation / etiology*
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Inflammation / metabolism
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Interleukin 1 Receptor Antagonist Protein / genetics
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Interleukin-1beta / immunology
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Interleukin-1beta / metabolism*
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Lymphocytes / immunology
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Lymphocytes / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic / immunology*
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Mice, Transgenic / metabolism
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Mice, Transgenic / virology
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Myeloid Cells / immunology*
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Precancerous Conditions / immunology
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Precancerous Conditions / metabolism
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Precancerous Conditions / pathology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Interleukin-1 / antagonists & inhibitors
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Receptors, Interleukin-1 / genetics
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Receptors, Interleukin-1 / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Stomach Neoplasms / etiology*
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Stomach Neoplasms / metabolism
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Stomach Neoplasms / pathology
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Transfection
Substances
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DNA-Binding Proteins
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Interleukin 1 Receptor Antagonist Protein
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Interleukin-1beta
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NF-kappa B
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RNA, Messenger
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Rag2 protein, mouse
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Receptors, Interleukin-1
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H(+)-K(+)-Exchanging ATPase