CXCL16
C-X-C motif chemokine 16 precursor (Scavenger receptor for phosphatidylserine and oxidized low density lipoprotein) (SR-PSOX) (Small-inducible cytokine B16) (Transmembrane chemokine CXCL16) [SCYB16] [SRPSOX] [UNQ2759/PRO6714]
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Inflammation in the liver provokes fibrosis, but inflammation is also important for tumor surveillance. Inhibitors of chemokine pathways, such as CXCL16 and CXCR6 regulation of lymphocyte trafficking, are being tested as antifibrotic agents, but their effects on the development of hepatocellular carcinoma (HCC) are unclear. We assessed the roles of CXCR6-dependent immune mechanisms in hepatocarcinogenesis. C57BL/6J wild-type (WT) mice and CXCR6-deficient mice (Cxcr6 ) were given injections of diethylnitrosamine (DEN) to induce liver cancer and α-galactosylceramide to activate natural killer T (NKT) cells. We also performed studies in mice with conditional, hepatocyte-specific deletion of NEMO, which develop inflammation-associated liver tumors (Nemo and Nemo Cxcr6 mice). We collected liver tissues from patients with cirrhosis (n = 43), HCC (n = 35), and neither of these diseases (control individuals, n = 25). Human and mouse liver tissues were analyzed by histology, immunohistochemistry, flow cytometry, RNA expression arrays (from sorted hepatic lymphocytes), and matrix-assisted laser desorption/ionization imaging. Bone marrow was transferred from Cxcr6 or WT mice to irradiated C57BL/6J mice, and spleen and liver cells were analyzed by flow cytometry. CD4 T cells or NKT cells were isolated from the spleen and liver of CD45.1 WT mice and transferred into CXCR6-deficient mice after DEN injection. After DEN injection, CXCR6-deficient mice had a significantly higher tumor burden than WT mice and increased tumor progression, characterized by reduced intrahepatic numbers of invariant NKT and CD4 T cells that express tumor necrosis factor and interferon gamma. Livers of Nemo Cxcr6 mice had significantly more senescent hepatocytes than livers of Nemo mice. In studies of bone-marrow chimeras, adoptive cell transfer experiments, and analyses of Nemo mice, we found that NKT and CD4 T cells promote the removal of senescent hepatocytes to prevent hepatocarcinogenesis, and that this process required CXCR6. Injection of WT with α-galactosylceramide increased removal of senescent hepatocytes by NKT cells. We observed peritumoral accumulation of CXCR6-associated lymphocytes in human HCC, which appeared reduced compared with cirrhosis tissues. In studies of mice with liver tumors, we found that CXCR6 mediated NKT-cell and CD4 T-cell removal of senescent hepatocytes. Antifibrotic strategies to reduce CXCR6 activity in liver, or to reduce inflammation or modulate the immune response, should be tested for their effects on hepatocarcinogenesis.
MeSH Terms
- Animals
- CD4-Positive T-Lymphocytes
- Carcinogenesis
- Carcinoma, Hepatocellular
- Cellular Senescence
- Diethylnitrosamine
- Disease Progression
- Galactosylceramides
- Hepatocytes
- Humans
- Immunologic Surveillance
- Interferon-gamma
- Intracellular Signaling Peptides and Proteins
- Liver Cirrhosis
- Liver Neoplasms
- Lymphocyte Activation
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Natural Killer T-Cells
- Receptors, CXCR6
- Tumor Burden
- Tumor Necrosis Factor-alpha
Keywords
- Chemokine
- Liver Cancer
- NKT Cells
- Senescence
As estrogen receptor β (ERβ ) mice age, the ventral prostate (VP) develops increased numbers of hyperplastic, fibroplastic lesions and inflammatory cells. To identify genes involved in these changes, we used RNA sequencing and immunohistochemistry to compare gene expression profiles in the VP of young (2-mo-old) and aging (18-mo-old) ERβ mice and their WT littermates. We also treated young and old WT mice with an ERβ-selective agonist and evaluated protein expression. The most significant findings were that ERβ down-regulates androgen receptor (AR) signaling and up-regulates the tumor suppressor phosphatase and tensin homolog (PTEN). ERβ agonist increased expression of the AR corepressor dachshund family (DACH1/2), T-cadherin, stromal caveolin-1, and nuclear PTEN and decreased expression of RAR-related orphan receptor c, Bcl2, inducible nitric oxide synthase, and IL-6. In the ERβ mouse VP, RNA sequencing revealed that the following genes were up-regulated more than fivefold: Bcl2, clusterin, the cytokines CXCL16 and -17, and a marker of basal/intermediate cells (prostate stem cell antigen) and cytokeratins 4, 5, and 17. The most down-regulated genes were the following: the antioxidant gene glutathione peroxidase 3; protease inhibitors WAP four-disulfide core domain 3 (WFDC3); the tumor-suppressive genes T-cadherin and caveolin-1; the regulator of transforming growth factor β signaling SMAD7; and the PTEN ubiquitin ligase NEDD4. The role of ERβ in opposing AR signaling, proliferation, and inflammation suggests that ERβ-selective agonists may be used to prevent progression of prostate cancer, prevent fibrosis and development of benign prostatic hyperplasia, and treat prostatitis.
MeSH Terms
- Aging
- Androgens
- Animals
- Chemokine CXCL16
- Chemokines, CXC
- Clusterin
- Down-Regulation
- Estrogen Receptor beta
- Interleukin-6
- Keratins
- Male
- Mice
- Mice, Knockout
- Nedd4 Ubiquitin Protein Ligases
- PTEN Phosphohydrolase
- Prostate
- Proto-Oncogene Proteins c-bcl-2
- Receptors, Androgen
- Signal Transduction
- Smad7 Protein
Keywords
- TGFβ
- cancer prevention
- inflammation
- nuclear receptor
Dendritic cells (DC) determine initiation, type and location of immune responses and, in adults, show decreased Toll-like receptors and some increased cytokine levels on ageing. Few studies in children have characterised DC or explored DC-related mechanisms producing age-related immune changes. The pDC marker BDCA2 (but not CD123) was absent in pre-pubertal children and numbers of pDC decreased with age. Blood and colonic DC were more mature and activated in adults. Decrease in pDC numbers correlated with reduced GM-CSF levels with aging, but increasing IL-4 and IL-8 levels correlated with a more activated DC profile in blood. CXCL16 levels decreased with age. Blood and colonic DC phenotypes were determined in healthy adults and children by flow cytometry and correlated with aging. Blood DC were divided into plasmacytoid (pDC) and myeloid (mDC) while only mDC were identified in colon. Serum cytokine levels were determined by multiplex cytokine assays and correlated with DC properties. In children, lack of BDCA2, a receptor mediating antigen capture and inhibiting interferon induction, may be immunologically beneficial during immune development. Conversely, reduced pDC numbers, probably secondary to decreasing GM-CSF and increasing cytokine-induced maturation of DC are likely to determine deteriorating immunity with ageing.
MeSH Terms
- Adult
- Age Factors
- Biomarkers
- Cell Differentiation
- Cells, Cultured
- Child
- Colon
- Cytokines
- Dendritic Cells
- Humans
- Myeloid Cells
Keywords
- BDCA-2
- Gerotarget
- aging
- children
- cytokines
- mDC
- pDC