THE FUNCTION AND REGULATION OF HISTIDINE DECARBOXYLASE IN GUT INFLAMMATION

组氨酸脱羧酶在肠道炎症中的作用及调控

• 批准号: 8241016
• 负责人: Timothy Cragin Wang
• 金额: $ 35.02万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-01-30 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8241016
• 关键词: Acids; Address; Biogenic Amines; Bone Marrow; Cancer Etiology; Cancer Model; Cell Differentiation process; Cell Lineage; Cell Maturation; Cell surface; Cells; Cholecystokinin; Cholecystokinin B Receptor; Chronic; Coculture Techniques; Colon Carcinoma; Colorectal; Colorectal Cancer; Data; Development; Down-Regulation; Enzymes; Epigenetic Process; Exhibits; Gene Expression; Green Fluorescent Proteins; Growth; Health; Histamine; Histamine Production; Histidine; Histidine Decarboxylase; Human; Hypersensitivity; IKBKB; ITGAM gene; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Inflammatory disease of the intestine; Interleukin-6; Knockout Mice; Laboratories; Lead; Leukocytes; Ligands; Link; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Mediating; Methylation; Modeling; Mus; Myelogenous; Myeloid Cells; Neoplasms; Phenotype; Physiological Processes; Physiology; Play; Predisposition; Receptor Signaling; Recruitment Activity; Regulation; Reporter; Role; S100A8 gene; Site; Staging; Stimulus; Suppressor-Effector T-Lymphocytes; Testing; Toxin; Transforming Growth Factor beta; Transgenic Organisms; Transplantation; Work; Xenograft Model; Xenograft procedure; cancer cell; cancer prevention; cancer site; cancer therapy; cancer type; carcinogenesis; cell growth; cell type; colon carcinogenesis; cytokine; granulocyte; in vivo; macrophage; monocyte; mouse model; neoplastic cell; neurotransmission; neutrophil; novel; novel marker; prevent; progenitor; promoter; recombinase; treatment strategy; tumor; tumor progression

DESCRIPTION (provided by applicant): The enzyme histidine decarboxylase (HDC) converts L-histidine to histamine, a biogenic amine that functions in numerous physiologic processes, but has increasingly been linked to immune regulation. Work from our laboratory using HDC-EGFP BAC transgenic reporter mice has demonstrated that HDC is highly expressed in CD11b+Ly6G+ immature myeloid cells (IMCs) that exhibit cell surface markers similar to myeloid-derived suppressor cells (MDSCs) or tumor-associated neutrophils (TAN). These HDC-expressing cells are recruited early on in an AOM/DSS model of colorectal carcinogenesis. HDC-/- mice that are deficient in histamine production exhibit markedly increased inflammatory responses to AOM/DSS and thus increased colon carcinogenesis, due largely to deficient myeloid maturation. HDC-/- mice show increased circulating CD11b+Ly6G+ IMCs and decreased mature neutrophils and macrophages, due to a requirement for histamine for normal maturation and differentiation of CD11b+Ly6G+ myeloid progenitors. Transplant of HDC deficient bone marrow to wild type recipients results in increased CD11b+Ly6G+ cell mobilization and reproduces the cancer susceptibility phenotype. CD11b+Ly6G+ IMCs from HDC-KO mice show increased proinflammatory cytokine expression and induce greater growth of colon cancer xenografts. IMCs accumulate in early stages of mouse and human colonic neoplasia, due to downregulation of HDC gene expression by cancer cells leading to inhibition of myeloid cell maturation, suggesting a novel mechanism by which tumors promote an active tumor microenvironment. Taken together, these data indicate key roles for HDC/histamine in myeloid cell differentiation, and CD11b+Ly6G+ IMCs in early colon cancer development. We are proposing four specific aims: (1) Are HDC-expressing CD11b+Gr1+ cells myeloid precursors that give rise to mature monocytes and granulocytes and other cell types? We will utilize HDC-BAC-Cre-ERTM mice developed in our laboratory to trace the development and differentiation of the myeloid cell lineage, both in vitro and in vivo. (2) How are HDC-expressing IMCs recruited during carcinogenic stimuli? We will examine the role of IL-1beta, IL-6, and RAGE ligands (S100A8/A9), and test the effect of IL-1beta blockade and RAGE deletion on IMC recruitment. (3) How do tumors downregulate HDC to inhibit myeloid cell differentiation and maturation? We will examine changes in methylation of the HDC CpG promoter sites during co-culture of IMCs with tumor cells, and explore the possible role of TGF-beta in modulating myeloid cell differentiation. (4) Are HDC-expressing IMC cells critical to the initiation and promotion of colorectal cancer? HDC-BAC-Cre-ERTM mice will be crossed to Ikkbeta F/F and DTR F/F mice, and we will also explore the importance of histamine in carcinogenesis.

描述（由申请人提供）：组氨酸脱羧酶（HDC）将L-组氨酸转化为组胺，组胺是一种在许多生理过程中发挥作用的生物胺，但越来越多地与免疫调节相关。我们实验室使用HDC-EGFP BAC转基因报告小鼠的工作表明，HDC在CD11b + Ly6G+未成熟髓样细胞（IMC）中高度表达，这些细胞表现出与髓源性抑制细胞（MDSC）或肿瘤相关中性粒细胞（TAN）相似的细胞表面标志物。这些表达HDC的细胞在结肠直肠癌发生的AOM/DSS模型中早期被招募。缺乏组胺产生的HDC-/-小鼠表现出对AOM/DSS的显著增加的炎症反应，从而增加结肠癌发生，这主要是由于缺乏骨髓成熟。HDC-/-小鼠表现出增加的循环CD11b + Ly6G + IMC和减少的成熟中性粒细胞和巨噬细胞，这是由于CD11b + Ly6G+骨髓祖细胞的正常成熟和分化需要组胺。将HDC缺陷型骨髓移植给野生型受体导致增加的CD11b + Ly6G+细胞动员并再现癌症易感性表型。来自HDC-KO小鼠的CD11b + Ly6G + IMC显示促炎细胞因子表达增加，并诱导结肠癌异种移植物的更大生长。由于癌细胞下调HDC基因表达导致骨髓细胞成熟抑制，IMC在小鼠和人结肠肿瘤形成的早期阶段积累，这表明肿瘤促进活跃的肿瘤微环境的新机制。总之，这些数据表明HDC/组胺在骨髓细胞分化中的关键作用，以及CD11b + Ly6G + IMC在早期结肠癌发展中的关键作用。我们提出了四个具体的目标：（1）表达HDC的CD11b + Gr 1+细胞是否是髓样前体细胞，可以产生成熟的单核细胞和粒细胞以及其他细胞类型？我们将利用我们实验室开发的HDC-BAC-Cre-ERTM小鼠在体外和体内追踪骨髓细胞谱系的发育和分化。(2)在致癌刺激过程中，表达HDC的IMC是如何被招募的？我们将检测IL-1 β、IL-6和β-内酰胺酶配体（S100A8/A9）的作用，并检测IL-1 β阻断和β-内酰胺酶缺失对IMC募集的影响。(3)肿瘤如何下调HDC以抑制髓样细胞分化和成熟？我们将研究在与肿瘤细胞共培养的IMCs过程中HDC CpG启动子位点甲基化的变化，并探讨TGF-β在调节髓系细胞分化中的可能作用。(4)表达HDC的IMC细胞对结直肠癌的发生和发展至关重要吗？HDC-BAC-Cre-ERTM小鼠将与Ikkbeta F/F和DTR F/F小鼠杂交，我们还将探索组胺在致癌作用中的重要性。