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Upregulation of cytokines and chemokines is a frequent finding in multiple myeloma (MM). CCL3 (also known as MIP-1α) is a pro-inflammatory chemokine, levels of which in the MM microenvironment correlate with osteolytic lesions and tumor burden. CCL3 and its receptors, CCR1 and CCR5, contribute to the development of bone disease in MM by supporting tumor growth and regulating osteoclast (OC) differentiation. In this study, we identify inhibition of osteoblast (OB) function as an additional pathogenic mechanism in CCL3-induced bone disease. MM-derived and exogenous CCL3 represses mineralization and osteocalcin production by primary human bone marrow stromal cells and HS27A cells. Our results suggest that CCL3 effects on OBs are mediated by ERK activation and subsequent downregulation of the osteogenic transcription factor osterix. CCR1 inhibition reduced ERK phosphorylation and restored both osterix and osteocalcin expression in the presence of CCL3. Finally, treating SCID-hu mice with a small molecule CCR1 inhibitor suggests an upregulation of osteocalcin expression along with OC downregulation. Our results show that CCL3, in addition to its known catabolic activity, reduces bone formation by inhibiting OB function, and therefore contributes to OB/OC uncoupling in MM.

MicroRNAs (miRNAs) are important host molecules involved in human immunodeficiency virus type 1 (HIV-1) infection. Antiretroviral therapy (ART) can affect the miRNA expression profile, but differentially expressed miRNAs still remain to be identified. In this study, we used gene chips to analyze miRNA expression profiles in peripheral blood mononuclear cells from ART-naive HIV-1 patients and those receiving ART, as well as from uninfected individuals. We measured differences in miRNA expression by quantitative polymerase chain reaction (qPCR) in an expanded sample. We found significant differences in the expression of has-miR-191-5p among the three groups (P < 0.05). Furthermore, we showed that hsa-miR-191-5p has an inhibitory effect on HIV-1 replication in cell models in vitro. We identified CCR1 and NUP50 as target molecules of hsa-miR-191-5p and found that hsa-miR-191-5p inhibits the expression of CCR1 and NUP50. Knockdown of NUP50 resulted in significant inhibition of HIV-1 replication. In summary, our research shows that hsa-miR-191-5p expression is reduced in HIV-1-infected patients and acts an inhibitor of HIV-1 infection via a mechanism that may involve targeted repression of NUP50 expression.

Mast cells are powerful immune cells found predominately in barrier tissues. They play an important role in immune surveillance and act as effector cells in allergic reactions. Mast cells develop from mast cell progenitors (MCp), which migrate to the peripheral tissues via the blood circulation. Presumably, the homing of MCp to the peripheral sites and localization is regulated by chemotactic signals. Due to the scarce abundance of these cells, chemotactic receptors have not been previously characterized on primary MCp. Here, mRNA transcripts for CCR1 and CX CR1 were identified in mouse bone marrow and lung MCp in a gene expression screen of chemotactic receptors. However, surface expression of CCR1 was only found in the bone marrow MCp. Flow cytometry-based screening identified distinct surface expression of CCR5 by mouse peritoneal mast cells and MCp, while surface expression of CXCR2-5, CX CR1, CCR1-3, CCR6-7, and CCR9 was not detected. Low surface expression of CCR5 was detected in mouse MCp in the bone marrow, spleen, and lung. To translate the findings to human, blood and bone marrow MCp from healthy donors were analyzed for possible CCR1 and CCR5 expression. Human MCp showed distinct surface expression of both CCR1 and CCR5. The expression levels of these chemokine receptors were higher in human bone marrow MCp than in the peripheral blood, suggesting that CCR1 and CCR5 may mediate retention in the bone marrow. In conclusion, mouse and human MCp show differential expression of CCR1 and CCR5 depending on their localization.

The main cause of death for colorectal cancer (CRC) patients is the development of metastatic lesions at sites distant from the primary tumor. Therefore, it is important to find biomarkers that are related to the metastasis and to study the possible mechanisms. Recent data have shown that soluble attractant molecules called chemokines support the metastasis of certain cancers to certain organs. To identify molecular regulators that are differentially expressed in liver metastasis of CRC, PCR array analysis was performed and CC chemokine ligand 7 (CCL7) showed remarkable overexpression in liver metastatic tumor tissues. To validate the results of the PCR array, 30 patients with primary CRC and liver metastases were selected. Immunohistochemistry and real-time PCR analysis showed that CCL7 was expressed in normal colonic epithelium and the expression was higher in liver metastases compared to primary CRC (P<0.001). Real-time PCR showed that the expression of CCR1, CCR2 and CCR3 was also higher in liver metastases compared to primary CRC (P=0.001, P=0.033 and P<0.001, respectively). In conclusion, correlation of CCL7 overexpression and its receptor expression with colon cancer liver metastasis suggests that CCL7 as a novel target in liver metastasis of CRC may be of potential clinical value for the prevention of hepatic recurrences.

The chemotactic response of murine peritoneal macrophages to RANTES/CCL5 was inhibited significantly following pretreatment with delta-9-tetrahydrocannabinol (THC), the major psychoactive component in marijuana. Significant inhibition of this chemokine directed migratory response was obtained also when the full cannabinoid agonist CP55940 was used. The CB 2 receptor-selective ligand O-2137 exerted a robust inhibition of chemotaxis while the CB 1 receptor-selective ligand ACEA had a minimal effect. The THC-mediated inhibition was reversed by the CB 2 receptor-specific antagonist SR144528 but not by the CB 1 receptor-specific antagonist SR141716A. In addition, THC treatment had a minimal effect on the chemotactic response of peritoneal macrophages from CB 2 knockout mice. Collectively, these results suggest that cannabinoids act through the CB 2 receptor to transdeactivate migratory responsiveness to RANTES/CCL5. Furthermore, the results suggest that the CB 2 receptor may be a constituent element of a network of G protein-coupled receptor signal transductional systems, inclusive of chemokine receptors, that act coordinately to modulate macrophage migration.

Chemokines and chemokine receptors play a role in migration of circulating leukocytes to the region of inflammation. Human LZIP is an uncharacterized transcription factor and is known to participate in leukotactin (Lkn)-1/CCL15-induced cell migration. We investigated the role of human LZIP in expression of CC chemokine receptors (CCRs) and its involvement in monocyte migration. RNase protection analysis showed that LZIP increased mRNA expression of CCR2 and CCR1 in THP-1 cells. Surface expressions of both CCR2 and CCR1 were also increased by LZIP. Results from an electrophoretic mobility shift assay showed that LZIP binds to the C/EBP element in the CCR2 promoter. LZIP also enhanced the chemotactic activities of monocyte chemoattractant protein-1/CCL2 and Lkn-1. These results suggest that LZIP regulates expression of chemokine receptors that are involved in monocyte migration.

Purpose To examine the migration responses of monocyte/macrophages (MO/MA) expressing complementary receptors to chemokines produced in the tumor environment of epithelial ovarian cancer (EOC). Methods We examined the expression of the chemokine receptors, CCR1, CCR5, and CXCR4, on EOC associated ascitic and blood MO/MA; their response to complementary chemokines in a MO/MA migration assay and the F-actin content in an actin polymerization assay. A validated cDNA microarray assay was then utilized to examine alterations in pathway genes that can be identified with cell migration. Results Ascitic and EOC blood MO/MA express CCR1, CCR5 and CXCR4, but differently. Cell surface expression levels for CCR1 and CCR5 were higher in ascites than that of normal blood in contrast to CXCR4 levels in ascitic MO/MA which were lower. EOC associated ascitic or blood MO/MA failed to migrate in response to the CC ligand RANTES and to the CXCR4 reactive chemokine, SDF1 (CXCL12). Ascitic and most EOC blood MO/MA also behaved differently from normal blood MO in the polymerization/depolymerization assay. A cDNA gene analysis of purified ascitic MO/MA demonstrated that a number of genes involved with chemokine production, focal adhesion, actin cytoskeletal function and leukocyte transendothelial migration were down-regulated in the ascitic MO/MA when compared to normal blood MO. Moreover, PBMC cDNA from EOC patients’ blood also showed gene profiles similar to that of ascitic MO/MA. Conclusions Defective migration and polymerization/depolymerization activity of MO/MA from EOC patients and a significant down-regulation of critical pathway genes suggest that other mechanisms might be involved in the accumulation of systemically derived MO at the tumor site of EOC patients.

Background Peanut is one of the most important oil and protein crops, and it exhibits wide cultivar variations in shoot Cd accumulation ability. However, the mechanism of Cd accumulation in peanut shoots has not been well understood. In this study, the root proteomics of two cultivars differing in seed Cd accumulation, Fenghua 1 (F, low Cd cultivar) and Silihong (S, high Cd cultivar), were investigated under 0 (CK) and 2 μM Cd conditions. Results A total of 4676 proteins were identified by proteomics screening. Of them, 375, 1762, 1276 and 771 proteins were identified to be differentially expressed proteins (DEPs) for comparison of F Cd /F CK , S Cd /S CK , F CK /S CK and F Cd /S Cd , respectively. Silihong is more sensitive to Cd exposure than Fenghua 1 in terms of root proteomics. A total of 30 and 86 DEPs were identified to be related with heavy metal transport and cell wall modification, respectively. The up-regulation of ABCB25, ABCC14, ABCC2, PDR1 and V-ATPases by Cd exposure in Silihong might enhance vacuolar sequestration of Cd and its efflux from symplast to apoplast. The higher Cd accumulation in the root CWs of Silihong might be resulted from its higher capability of CW modification, in which many proteins such as IRX10L, BGLU12-like, BGLU42, EXLB1, XTH30, XTH6, XYL7, PAL3, COMT, CAD1, and CCR1 were involved. Conclusions The vacuolar sequestration and efflux of Cd as well as its adsorption in CW might be the principal mechanism of cadmium detoxification in Silihong. The higher capacity of Cd accumulation and translocation of Silihong is an inherent characteristics in which ACA8 and ZIP1 might be involved.

Stone cells negatively affect fruit quality because of their firm and lignified cell walls, so are targets for reduction in pear breeding programmes. However, there is only limited knowledge of the molecular mechanisms underlying the formation of stone cells. Here, we show that PbrMYB169, an R2R3 MYB transcription factor, of Pyrus bretschneideri positively regulates lignification of stone cells in pear fruit. PbrMYB169 was shown to be co-expressed with lignin biosynthesis genes during pear fruit development, and this co-expression pattern was coincident with stone cell formation in the fruit of Pyrus bretschneideri ‘Dangshansuli’. The PbrMYB169 expression level was also positively correlated with stone cell content in 36 pear cultivars tested. PbrMYB169 protein significantly activated the promoter of lignin genes C3H1, CCR1, CCOMT2, CAD, 4CL1, 4CL2, HCT2, and LAC18 via binding to AC elements [ACC(T/A)ACC] in these promoters. Furthermore, overexpression of PbrMYB169 in transgenic Arabidopsis plants enhanced the expression of lignin genes, and increased lignin deposition and cell wall thickness of vessel elements, but did not change the ratio of syringyl and guaiacyl lignin monomers. In conclusion, PbrMYB169 appears to be a transcriptional activator of lignin biosynthesis and regulates secondary wall formation in fruit stone cells. This study advances the understanding of the regulation of lignin biosynthesis and provides valuable molecular genetic information for reducing stone cell content in pear fruit.

CCL23, also known as myeloid progenitor inhibitory factor (MPIF)-1, macrophage inflammatory protein (MIP)-3, or CKβ8, is a member of the CC chemokine subfamily exerting its effects via CCR1 binding. By doing so, CCL23 selectively recruits resting T lymphocytes and monocytes, inhibits proliferation of myeloid progenitor cells and promotes angiogenesis. Previously, we and other groups have reported that human neutrophils are able to produce chemokines upon appropriate activation, including CCR1-binding CCL2, CCL3, and CCL4. Herein, we demonstrate that human neutrophils display the capacity to also express and release CCL23 when stimulated by R848 and, to a lesser extent, by other pro-inflammatory agonists, including LPS, Pam3CSK4, and TNFα. Notably, we show that, on a per cell basis, R848-activated neutrophils produce higher levels of CCL23 than autologous CD14 -monocytes activated under similar experimental conditions. By contrast, we found that, unlike CD14 -monocytes, neutrophils do not produce CCL23 in response to IL-4, thus indicating that they express CCL23 in a stimulus-specific fashion. Finally, we show that the production of CCL23 by R848-stimulated neutrophils is negatively modulated by IFNα, which instead enhances that of CCL2. Together, data extend our knowledge on the chemokines potentially produced by neutrophils. The ability of human neutrophils to produce CCL23 further supports the notion on the neutrophil capacity of orchestrating the recruitment of different cell types to the inflamed sites, in turn contributing to the control of the immune response.