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MIP-1
Selected AbstractsOver-expression of CCL3,,MIP-1, in a blastoid mantle cell lymphoma with hypercalcemiaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 5 2010Norimichi Hattori Abstract We analyzed a case with the blastoid variant of mantle cell lymphoma (MCL-BV), a rare subtype of B-cell lymphoma, presenting with marked hypercalcemia at diagnosis. Enzyme-linked immunosorbent assay (ELISA) showed elevated serum levels of interleukin-6 (IL-6), tumor necrosis factor-, (TNF-,), macrophage inflammatory protein-1, (MIP-1,), and type I collagen telopeptide, but not parathyroid hormone, calcitriol or parathyroid hormone-related peptide at diagnosis, suggesting local osteoclastic hypercalcemia in this case. By reverse transcription polymerase chain reaction (RT-PCR) analysis, we found predominant expression of mRNA for MIP-1, in addition to those for receptor-activator of nuclear-factor kappa B ligand (RANKL), TNF-,, and IL-6 in lymphoma cells obtained from the patient. Furthermore, recombinant MIP-1, significantly stimulated 3H-thymidine uptake by isolated MCL cells in vitro. Treatment with intravenous fluids, bisphosphonate, and methylprednisolone followed by combination chemotherapy promptly corrects the hypercalcemia and successfully induced complete remission, which was accompanied by a decrease of these cytokines in the serum, including MIP-1,. In the present case, MIP-1,, an osteoclast-activating factor produced by mantle lymphoma cells, may contribute to the development of hypercalcemia. It likely acts through RANKL expression in tumor cells and/or stroma cells, as indicated in multiple myeloma (MM) and adult T-cell leukemia/lymphoma (ATLL). Furthermore, MIP-1, is also involved in the development of an aggressive phenotype on MCL by stimulating proliferation of these lymphoma cells. In summary, the present study demonstrated that MIP-1, is an important factor in the development of both hypercalcemia and an aggressive phenotype in some types of B-cell lymphoma. [source] Suppression of viral replication with highly active antiretroviral therapy has no impact on the functional profile of HIV-specific CD8+ T cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2008Mariola López Abstract A better control of viral replication in long-term non-progressors has been associated with polyfunctional CD8+ T cell responses. However, low levels of HIV replication could be the cause rather than the consequence of enhanced immune responses in long-term non-progressors. The functional profile and the expansion ability of HIV-Gag- and HIV-Nef-specific CD8 responses were analysed measuring the production of MIP-1,, IL-2, TNF-, and expression of CD107, using polychromatic flow cytometry, in 36,HIV-infected patients at baseline and after 12,months of highly active antiretroviral therapy (HAART) and complete viral suppression. Most patients presented detectable Gag and Nef responses both at baseline and after 1,year of HAART, with a significant decline after achieving viral suppression. At baseline, the majority of CD8+ response was due to cells producing only MIP-1, or simultaneously MIP-1, and CD107. The functional profile did not significantly change after achieving complete viral suppression with HAART. Therefore, control of HIV-1 replication after 1,year of HAART had no significant impact on the quality of HIV-1-specific CD8 response, but the effects of treatment in long-term, or of early HAART are not known. Thus, it is still uncertain whether multifunctional CD8 responses are the cause or consequence of low plasma viremia. [source] A novel form of NF-,B is induced by Leishmania infection: Involvement in macrophage gene expressionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2008David Abstract Leishmania spp. are obligate intracellular parasites that inhabit the phagolysosomes of macrophages. Manipulation of host cell signaling pathways and gene expression by Leishmania is critical for Leishmania's survival and resultant pathology. Here, we show that infection of macrophages with Leishmania promastigotes in vitro causes specific cleavage of the NF-,B p65RelA subunit. Cleavage occurs in the cytoplasm and is dependent on the Leishmania protease gp63. The resulting fragment, p35RelA, migrates to the nucleus, where it binds DNA as a heterodimer with NF-,B p50. Importantly, induction of chemokine gene expression (MIP-2/CXCL2, MCP-1/CCL2, MIP-1,/CCL3, MIP-1,/CCL4) by Leishmania is NF-,B dependent, which implies that p35RelA/p50 dimers are able to activate transcription, despite the absence of a recognized transcriptional transactivation domain. NF-,B cleavage was observed following infection with a range of pathogenic species, including L.,donovani, L.,major, L.,mexicana, and L.,(Viannia) braziliensis, but not the non-pathogenic L.,tarentolae or treatment with IFN-,. These results indicate a novel mechanism by which a pathogen can subvert a macrophage's regulatory pathways to alter NF-,B activity. [source] Immunisation with BCG and recombinant MVA85A induces long-lasting, polyfunctional Mycobacterium tuberculosis -specific CD4+ memory T lymphocyte populationsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2007Natalie Abstract In the search for effective vaccines against intracellular pathogens such as HIV, tuberculosis and malaria, recombinant viral vectors are increasingly being used to boost previously primed T cell responses. Published data have shown prime-boost vaccination with BCG-MVA85A (modified vaccinia virus Ankara expressing antigen 85A) to be highly immunogenic in humans as measured by ex vivo IFN-, ELISPOT. Here, we used polychromatic flow cytometry to investigate the phenotypic and functional profile of these vaccine-induced Mycobacterium tuberculosis (M.tb) antigen 85A-specific responses in greater detail. Promisingly, antigen 85A-specific CD4+ T cells were found to be highly polyfunctional, producing IFN-,, TNF-,, IL-2 and MIP-1,. Surface staining showed the responding CD4+ T cells to be relatively immature (CD45RO+ CD27intCD57,); this observation was supported by the robust proliferative responses observed following antigenic stimulation. Furthermore, these phenotypic and functional properties were independent of clonotypic composition and epitope specificity, which was maintained through the different phases of the vaccine-induced immune response. Overall, these data strongly support the use of MVA85A in humans as a boosting agent to expand polyfunctional M.tb -specific CD4+ T cells capable of significant secondary responses. [source] Neutrophil recruitment in immunized mice depends on MIP-2 inducing the sequential release of MIP-1,, TNF-, and LTB4EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2006Cleber Abstract Neutrophils are thought to play an important role in the tissue damage observed in various autoimmune diseases. Chemokines, cytokines and leukotrienes have recognized roles in the orchestration of neutrophil migration. We have recently shown that antigen-induced neutrophil migration into the peritoneum of immunized mice is mediated by macrophage-inflammatory protein (MIP)-1, which interacts with CCR1 and induces the sequential release of TNF-, and leukotriene,B4 (LTB4). The present study investigates the role of MIP-2 and CXCR2 in the cascade of events leading to mediator generation and neutrophil influx. Antigen challenge of immunized mice induced the expression of CXCR2 and the production of KC and MIP-2 proteins. Antigen-induced neutrophil migration was inhibited by a CXCR2 receptor antagonist (repertaxin) or an anti-MIP-2 antibody, but not by an anti-KC antibody. Administration of MIP-2 promoted a dose-dependent neutrophil migration in naive mice which was inhibited by repertaxin, anti-TNF-,, anti-MIP-1, antibodies or by MK886 (leukotriene synthesis inhibitor). MIP-2 administration induced the release of MIP-1,, TNF-, and LTB4, and the release of the latter two was inhibited by anti-MIP-1, antibody treatment. Our studies highlight the intricate balance between mediator production and action during an immune-mediated inflammatory response and suggest a mediator cascade leading to neutrophil influx following antigen challenge of immunized mice: MIP-2 , MIP-1, , TNF-, , LTB4. [source] Recruitment of different subsets of antigen-presenting cells selectively modulates DNA vaccine-elicited CD4+ and CD8+ T lymphocyte responsesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2004Abstract The immunogenicity of plasmid DNA vaccines may be limited by the availability of professional antigen-presenting cells (APC) at the site of inoculation. Here we demonstrate that the types of APC recruited to the injection site can selectively modulate CD4+ or CD8+ T lymphocyte responses elicited by an HIV-1 Env DNA vaccine in mice. Coadministration of plasmid GM-CSF with the DNA vaccine resulted in the recruitment of macrophages to the site of inoculation and specifically augmented vaccine-elicited CD4+ T lymphocyte responses. In contrast, coadministration of plasmid MIP-1, with the DNA vaccine resulted in the recruitment of dendritic cells to the injection site and enhanced vaccine-elicited CD8+ T lymphocyte responses. Interestingly, coadministration of both plasmid GM-CSF and plasmid MIP-1, with the DNA vaccine recruited both macrophages and dendritic cells and led to a synergistic and sustained augmentation of CD4+and CD8+ T lymphocyte responses. These data demonstrate the critical importance of locally recruited professional APC in determining the magnitude and nature of immune responses elicited by plasmid DNA vaccines. Moreover, these studies show that different subsets of professional APC can selectively modulate DNA vaccine-elicited T lymphocyte responses. [source] Increased levels of inflammatory chemokines in amyotrophic lateral sclerosisEUROPEAN JOURNAL OF NEUROLOGY, Issue 6 2009J. Kuhle Background and purpose:, Amyotrophic lateral sclerosis (ALS) is classically assumed to be a neurodegenerative disorder. Inflammation has been observed in CNS tissue in ALS patients. We investigated the expression and prognostic relevance of proinflammatory chemokines in ALS. Methods:, We analyzed nine chemokines, eotaxin, eotaxin-3, IL-8, IP-10, MCP-1, MCP-4, macrophage derived chemokine (MDC), macrophage inflammatory protein-1, (MIP-1,), and serum thymus and activation- regulated chemokine (TARC) in serum and cerebrospinal fluid (CSF) of 20 ALS- and 20 non-inflammatory neurological disease (NIND)-patients. Results:, MCP-1 and IL-8 levels in CSF in ALS were significantly higher than in NIND (1304 pg/ml vs. 1055 pg/ml, P = 0.013 and 22.7 pg/ml vs. 18.6 pg/ml, P = 0.035). The expression of MCP-1 and IL-8 were higher in CSF than in serum (P < 0.001). There was a trend towards higher MCP-1 CSF levels in ALS patients with shorter time between first symptoms and diagnosis (r = ,0.407; P = 0.075). Conclusions:, We confirmed previous findings of increased MCP-1 levels in CSF of ALS patients. Furthermore, increased levels of IL-8 in CSF suggest a stimulation of a proinflammatory cytokine cascade after microglia activation. We found a tendency for higher MCP-1 values in patients with a shorter diagnostic delay, who are known to have also a shorter survival. This may suggest an association of higher MCP-1 levels with rapidly progressing disease. [source] Interferon-, differentially modulates the release of cytokines and chemokines in lipopolysaccharide- and pneumococcal cell wall-stimulated mouse microglia and macrophagesEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2002Karl Georg Häusler Abstract During bacterial infections of the CNS, activated microglia could support leucocyte recruitment to the brain through the synthesis of cyto- and chemokines. In turn, invading leucocytes may feedback on microglial cells to influence their chemokine release pattern. Here, we analyzed the capacity of interferon-, (IFN,) to serve as such a leucocyte-to-microglia signal. Production of cyto- and chemokines was stimulated in mouse microglia cultures by treatments with lipopolysaccharide (LPS) from Gram-negative Escherichia coli or cell walls from Gram-positive Streptococcus pneumoniae (PCW). IFN, presence during the stimulation (0.1,100 ng/mL) modulated the patterns of LPS- and PCW-induced cyto- and chemokine release in a dose-dependent, potent and complex manner. While amounts of TNF, and IL-6 remained nearly unchanged, IFN, enhanced the production of IL-12, MCP-1 and RANTES, but attenuated that of KC, MIP-1, and MIP-2. Release modulation was obtained with IFN, preincubation (treatment of cells before LPS or PCW administration), coincubation and even delayed addition to an ongoing LPS or PCW stimulation. Together the changes observed for the microglial chemokine release under IFN, would shift the chemoattractive profile from favouring neutrophils to a preferential attraction of monocytes and T lymphocyte populations , as actually seen during the course of bacterial meningitis. The findings support the view of activated microglia as a major intrinsic source for an instant production of a variety of chemokines and suggest that leucocyte-derived IFN, could potentially regulate the microglial chemokine release pattern. [source] Pigment epithelium-derived factor induces the production of chemokines by rat microgliaGLIA, Issue 4 2005Asako Takanohashi Abstract Many studies have shown that pigment epithelium-derived factor (PEDF) has neurotrophic effects on retinal cells and hippocampal, spinal cord, and cerebellar granule cell neurons, but much less work has examined the effects of PEDF on glia. In this study, we show that PEDF changes microglial morphology within 1 h of exposure, to a more deactivated form, while having no effect on the expression of such activation markers as OX-42 and ED-1. In contrast, urea activates acid phosphatase, and PEDF blocks that activation. PEDF also activates NF,B, accompanied by the induction of mRNAs and proteins for the chemokines macrophage inflammatory protein-1, (MIP-1,, MIP-2, and MIP-3,. All the chemokines stimulate acid phosphatase activity, and high doses of MIP-2 and MIP-3,), alter the morphology of the microglia at 1 h after treatment. These results suggest that the use of PEDF for clinical treatments, such as for retinal neovascularization, brain injury, or ischemia, should be undertaken with caution because of the possibility of induction of inflammation caused by microglial or other immune cell migration in response to the chemokines induced by PEDF. © 2005 Wiley-Liss, Inc. [source] RANTES stimulates inflammatory cascades and receptor modulation in murine astrocytesGLIA, Issue 1 2002Yi Luo Abstract Cultured mouse astrocytes respond to the CC chemokine RANTES by production of chemokine and cytokine transcripts. Stimulation of astrocytes with 1 nM RANTES or 3,10 nM of the structurally related chemokines (eotaxin, macrophage inflammatory protein-1, and -, [MIP-1,, MIP-1,]) induced transcripts for KC, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-, (TNF-,), MIP-1,, MIP-2, and RANTES in a chemokine and cell-specific fashion. Synthesis of chemokine (KC and MCP-1) and cytokine (TNF-,) proteins was also demonstrated. RANTES-mediated chemokine synthesis was specifically inhibited by pertussis toxin, indicating that G-protein-coupled chemokine receptors participated in astrocyte signaling. Astrocytes expressed CCR1 and CCR5 (the redundant RANTES receptors). Astrocytes derived from mice with targeted mutations of either CCR1 or CCR5 respond after RANTES stimulation, suggesting multiple chemokine receptors may separately mediate RANTES responsiveness in astrocytes. Preliminary data suggest activation of the MAP kinase pathway is also critical for RANTES-mediated signaling in astrocytes. Treatment with RANTES specifically modulated astrocyte receptors upregulating intercellular adhesion molecule 1 (ICAM-1) and downregulating CX3CR1 expression. Thus, after chemokine treatment, astrocytes release proinflammatory mediators and reprogram their surface molecules. The combined effects of RANTES may serve to amplify inflammatory responses within the central nervous system. GLIA 39:19,30, 2002. © 2002 Wiley-Liss, Inc. [source] Isolated human astrocytes are not susceptible to infection by M- and T-tropic HIV-1 strains despite functional expression of the chemokine receptors CCR5 and CXCR4 ,GLIA, Issue 3 2001Agnčs Boutet Abstract Within the brain, HIV-1 targets the microglia and astrocytes. Previous studies have reported that viral entry into astrocytes is independent of CD4, in contrast to microglia. We aimed to determine whether chemokine receptors play a role in mediating CD4-independent HIV-1 entry into astrocytes. We found that embryonic astrocytes and microglial cells express CCR5, CCR3, and CXCR4 transcripts. Intracellular calcium levels in astrocytes were found to increase following application of RANTES, MIP-1, (CCR5-agonist), SDF-1, (CXCR4-agonist), but not eotaxin (CCR3-agonist). In microglial cells, eotaxin was also able to modulate internal calcium homeostasis. CD4 was not present at the cell surface of purified astrocytes but CD4 mRNA could be detected by RT-PCR. Neither HIV-19533 (R5 isolate) nor HIV-1LAI (X4 isolate) penetrated into purified astrocytes. In contrast, mixed CNS cell cultures were infected by HIV-19533 and this was inhibited by anti-CD4 mAb in 4/4 tested cultures and by anti-CCR5 mAb in 2/4. Thus, the HIV-1 R5 strain requires CD4 to penetrate into brain cells, suggesting that CCR5 cannot be used as the primary receptor for M-tropic HIV-1 strains in astrocytes. Moreover, inconstant inhibition of HIV-1 entry by anti-CCR5 mAb supports the existence of alternative coreceptors for penetration of M-tropic isolates into brain cells. GLIA 34:165,177, 2001. © 2001 Wiley-Liss, Inc. [source] Oral biopsies from patients with orofacial granulomatosis with histology resembling Crohn's disease have a prominent Th1 environmentINFLAMMATORY BOWEL DISEASES, Issue 4 2007Jona Freysdottir BSc Abstract Background: Orofacial granulomatosis (OFG) is an idiopathic inflammatory disorder of children and young adults whose clinical symptoms include swelling of the lips or face, mucosal nodularity (cobblestoning), mucosal tags, hyperplasia of the gingivae, and aphthous oral ulcers. Whether some OFG patients with clinical and histological characteristics resembling Crohn's disease (CD) are a special group (oral CD) or true CD patients with symptoms reaching all the way to the oral mucosa remains to be determined. Methods: In this study oral biopsies from 10 patients with OFG were analyzed for the presence of T cells, T-cell subsets, B cells, and macrophages, as well as cytokines (IL-4, IL-10, IFN-,, IL-12, and TNF-,), chemokines (RANTES and MIP-1,), and chemokine receptors (CCR3, CCR5, and CXCR3). For comparison, oral tissues from 7 patients with other granulomatous diseases were included. Results: Compared with the non-OFG group, the OFG group had raised levels of CD4+ T cells, IFN-,, IL-10, and RANTES but reduced levels of CD68+ macrophages outside the granulomas, whereas within the granulomas the levels of CD3+ and CD4+ T cells and of IFN-, were raised, but the levels of IL-4 were decreased. These data are indicative of a Th1 environment within the oral OFG tissues, which resembles that already observed in gut CD tissues. Conclusions: Therefore, it can be concluded that some OFG patients have both histopathological and immunopathological features that resemble those observed in CD patients. (Inflamm Bowel Dis 2006) [source] Stromal MCP-1 in mammary tumors induces tumor-associated macrophage infiltration and contributes to tumor progressionINTERNATIONAL JOURNAL OF CANCER, Issue 6 2009Hiroshi Fujimoto Abstract There is growing evidence that tumor-associated macrophages (TAMs) promote tumor growth and dissemination. Many individual reports have focused on the protumor function of molecules linked to the recruitment of macrophages, but little is known about which factor has the strongest impact on recruitment of macrophages in breast cancer. To elucidate this question, we performed RT-PCR using species-specific primers and evaluated tumoral and stromal mRNA expression of macrophage chemoattractants separately in human breast tumor xenografts. The correlation between the tumoral or stromal chemoattractant mRNA expression including monocyte chemoattractant protein-1 (MCP-1) (CCL2), MIP-1, (CCL3), RANTES (CCL5), colony-stimulating factor 1, tumor necrosis factor ,, platelet-derived growth factor (PDGF)-BB and macrophage infiltration were compared. There was significant positive correlation between stromal MCP-1 expression and macrophage number (r = 0.63), and negative correlation between tumoral RANTES expression and macrophage number (r = ,0.75). However, no significant correlation was found for the other tumoral and stromal factors. The interaction between the tumor cells and macrophages was also investigated. Tumor cell,macrophage interactions augmented macrophage-derived MCP-1 mRNA expression and macrophage chemotactic activity in vitro. Treatment of immunodeficient mice bearing human breast cancer cells with a neutralizing antibody to MCP-1 resulted in significant decrease of macrophage infiltration, angiogenetic activity and tumor growth. Furthermore, immunohistochemical analysis of human breast cancer tissue showed stromal MCP-1 had a significant correlation with relapse free survival (p = 0.029), but tumoral MCP-1 did not (p = 0.105). These findings indicate that stromal MCP-1 produced as a result of tumor,stromal interactions may be important for the progression of human breast cancer and macrophages may play an important role in this tumor,stroma interaction. © 2009 UICC. [source] New molecular markers of early and progressive CJD brain infectionJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2004Zhi Yun Lu Abstract Transmissible spongiform encephalopathies (TSEs), including human Creutzfeldt,Jakob disease (CJD), are caused by a related group of infectious agents that can be transmitted to many mammalian species. Because the infectious component of TSE agents has not been identified, we examined myeloid cell linked inflammatory pathways to find if they were activated early in CJD infection. We here identify a specific set of transcripts in CJD infected mouse brains that define early and later stages of progressive disease. Serum amyloid A3 and L-selectin mRNAs were elevated as early as 20 days after intracerebral inoculation. Transcripts of myeloid cell recruitment factors such as MIP-1,, MIP-1,, and MCP1, as well as IL1, and TNF, were upregulated >10 fold between 30 and 40 days, well before prion protein (PrP) abnormalities that begin only after 80 days. At later stages of symptomatic neurodegenerative disease (100,110 days), a selected set of transcripts rose by as much as 100 fold. In contrast, normal brain inoculated controls showed no similar sequential changes. In sum, rapid and simple PCR tests defined progressive stages of CJD brain infection. These markers may also facilitate early diagnosis of CJD in accessible peripheral tissues such as spleen and blood. Because some TSE strains can differentially target particular cell types such as microglia, several of these molecular changes may also distinguish specific agent strains. The many host responses to the CJD agent challenge the assumption that the immune system does not recognize TSE infections because these agents are composed only of the host's own PrP. © 2004 Wiley-Liss, Inc. [source] Matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1 in the respiratory tracts of human infants following paramyxovirus infectionJOURNAL OF MEDICAL VIROLOGY, Issue 4 2007Matthew B. Elliott Abstract Respiratory syncytial (RSV) and parainfluenza (PIV) viruses are primary causes of acute bronchiolitis and wheezing illnesses in infants and young children. To further understand inflammation in the airways following infection, we tested for the presence of matrix metalloproteinases (MMP) and natural tissue inhibitors of MMP (TIMP) in primary and established human cell lines, and in the nasopharyngeal secretions (NPS) of human infants infected with RSV or PIV. Using ELISA and multiplex-based assays, MMP-9 and TIMP-1 proteins were, respectively, detected in 66/67 and 67/67 NPS. During PIV or RSV infection TIMP-1 concentrations were associated with hypoxic bronchiolitis. TIMP-1 amounts were also negatively correlated with O2 saturation, and positively correlated with IL-6, MIP-1,, and G-CSF amounts following RSV infection. IL-6, MIP-1,, and G-CSF were negatively correlated with O2 saturation during RSV infection. Acute respiratory tract disease was not associated with MMP-9 protein/protease activity. Additional studies using real-time quantitative PCR suggested that MMP-9 mRNA copy numbers were elevated in normal human bronchial epithelial (NHBE) cells infected with RSV, while TIMP-1 and TIMP-2 were not increased. However, ELISA did not reveal MMP-9 protein in the NHBE cell culture supernatants. Hence, the data implied that airway epithelial cells were not the primary source of MMP or TIMP following paramyxovirus infection. Taken together, the data suggested that paramyxovirus infection perturbs MMP-9/TIMP-1 homeostasis that in turn may contribute to the severity of respiratory tract disease. J. Med. Virol. 79:447,456, 2007. © 2007 Wiley-Liss, Inc. [source] A comparison of epidemiologic and immunologic features of bronchiolitis caused by influenza virus and respiratory syncytial virusJOURNAL OF MEDICAL VIROLOGY, Issue 2 2005Roberto P. Garofalo Abstract We studied epidemiologic and immunologic factors in infants with bronchiolitis caused by influenza virus. The proportion of these infants who were male and who had an immediate family member with a history of asthma was similar to that of a control group of infants with respiratory syncytial virus (RSV) bronchiolitis. In subjects with influenza virus infection, concentrations of the beta chemokine macrophage inflammatory protein-1alpha (MIP-1,), but not other beta chemokines, in nasopharyngeal secretions (NPS) were greater among infants with more severe, hypoxic bronchiolitis than in subjects with mild, nonhypoxic bronchiolitis, or upper respiratory tract infection alone. Quantities of MIP-1, were also correlated with lower values of oxygen saturation. These findings point out epidemiologic and immunologic similarities between bronchiolitis caused by influenza and RSV, and suggest that host factors are more important than the nature of the infecting virus in the development of severe forms of bronchiolitis caused by influenza and RSV. J. Med. Virol. 75:282,289, 2005. © 2004 Wiley-Liss, Inc. [source] The role of inflammatory mediators in the pathophysiology of X-ALD diseaseJOURNAL OF NEUROCHEMISTRY, Issue 2002A. S. Paintlia CER is the most frequent clinical phenotype of the defective X-ALD (ALD; ABCD1) gene, which results in accumulation of VLCFAs (in plasma, brain, adrenal glands and testis), inflammatory demyelination and subsequent death in children. To understand the inflammatory mediators that play a role in the neuropathology of CER, we studied mRNA expressions of inflammatory mediators in CER brain by using super gene array. Total of nine tissue slices were taken from three different locations from CER brain starting with plaque, demyelinating edge (Plaque shadow) and normal looking area. Histopathological examinations showed intensive demyelination in plaque region and accumulation of infiltrates (Macrophages and T lymphocytes) in plaque and plaque shadow as compared to normal looking area. Biochemical studies indicated significant increase in the levels of VLCFAs (26 : 0) in plaque and plaque shadow regions in comparison to normal looking area. There was significant increase in the levels of inflammatory cytokines (IL-1,, TNF-, and IL-6) in plaque shadow as compared with normal looking area and control brain tissue region. Other cytokines like IL-2, IL-3, GM-CSF, IL-11, IL-12A were found to be increased significantly (p < 0.01) in plaque shadow. There was significant (p < 0.01) increase in the expression chemokines; MCP-1, MCP-3, MIP-1, and MIP-2 in the plaque shadow in comparison with normal looking area of CER brain. Chemokines; Fractalkine, Eotaxin, SDF-2, MDC-2, HCC-4 were also observed to be higher in plaque shadow. Data was further evaluated using RT,PCR for MCP-1 and CCR-2, which showed elevated levels in plaque and plaque shadow. This study identified a group of inflammatory mediators that may play a role in pathophysiology of X-ALD disease. Acknowledgements:, Supported by grants; NS-22526, NS-34741, NS-37766 and NS-40810. [source] An anti-inflammatory oligopeptide produced by Entamoeba histolytica down-regulates the expression of pro-inflammatory chemokinesPARASITE IMMUNOLOGY, Issue 10 2003Dolores Utrera-Barillas SUMMARY Axenically grown Entamoeba histolytica produces a pentapeptide (Met-Gln-Cys-Asn-Ser) with anti-inflammatory properties that, among others, inhibits the in vitro and in vivo locomotion of human monocytes, sparing polymorphonuclear leucocytes from this effect [hence the name originally given: Monocyte Locomotion Inhibitory Factor (MLIF)]. A synthetic construct of this peptide displays the same effects as the native material. We now added MLIF to resting and PMA-stimulated cells of a human monocyte cell line and measured the effect upon mRNA and protein expression of pro-inflammatory chemokines (RANTES, IP-10, MIP-1,, MIP-1,, MCP-1, IL-8, I-309 and lymphotactin) and the shared CC receptor repertoire. The constitutive expression of these chemokines and the CC receptors was unaffected, whereas induced expression of MIP-1,, MIP-1,, and I-309, and that of the CCR1 receptor , all involved in monocyte chemotaxis , was significantly inhibited by MLIF. This suggests that the inhibition of monocyte functions by MLIF may not only be exerted directly on these cells, but also , and perhaps foremost , through a conglomerate down-regulation of endogenous pro-inflammatory chemokines. [source] Chemokine and cytokine expression in murine intestinal epithelium following Nippostrongylus brasiliensis infectionPARASITE IMMUNOLOGY, Issue 2 2002Anne Rosbottom Summary Infection of mice with the nematode parasite Nippostrongylus brasiliensis results in a well characterized intestinal mastocytosis with intraepithelial migration of mucosal mast cells (MMC). The molecules mediating this response are unknown. We examined expression of several putative mast cell chemoattractants in intestinal epithelium following N. brasiliensis infection. Expression of the chemokines monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1,(MIP-1,), RANTES (regulated on activation normal T-cell expressed and secreted), fractalkine, and thymocyte expressed chemokine (TECK); and the cytokines stem cell factor (SCF) and transforming growth factor ,1 (TGF,1), was constitutive and no alteration was detected following infection. MCP-1 expression was also constitutive but at much lower levels and increased expression was detected on days 7 and 14 postinfection. Expression of MCP-1 in whole jejunum was at much higher levels than in epithelium. Constitutive expression of MCP-1, MIP-1, and TGF,1 was also detected in cultured bone marrow-derived homologues of MMC. In an intestinal epithelial cell line (CMT-93), there was constitutive expression of SCF, TGF,1, fractalkine and MCP-1. The results show that, in vivo, epithelium is a potentially important source of mast cell chemoattractants. [source] Secreted proteome of the murine multipotent hematopoietic progenitor cell line DKmixRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 5 2010Nina Luecke Administration of the multipotent hematopoietic progenitor cell (HPC) line DKmix improved cardiac function after myocardial infarction and accelerated dermal wound healing due to paracrine mechanisms. The aim of this study was to analyse the secreted proteins of DKmix cells in order to identify the responsible paracrine factors and assess their relevance to the wide spectrum of therapeutic effects. A mass spectrometry (MS)-based approach was used to identify secreted proteins of DKmix cells. Serum free culture supernatants of DKmix-conditioned medium were collected and the proteins present were separated, digested by trypsin and the resulting peptides were then analyzed by matrix-assisted laser desorption/ionization tandem time-of-flight (MALDI-TOF/TOF) MS. Overall 95 different proteins were identified. Among them, secretory proteins galectin-3 and gelsolin were identified. These proteins are known to stimulate cell migration and influence wound healing and cardiac remodelling. The remaining proteins originate from intracellular compartments like cytoplasm (69%), nucleus (12%), mitochondria (4%), and cytoplasmic membrane (3%) indicating permeable or leaky DKmix cells in the conditioned medium. Additionally, a sandwich immunoassay was used to detect and quantify cytokines and chemokines. Interleukin-6 (IL-6), interleukin-13 (IL-13), monocyte-chemoattractant protein-1 (MCP-1), monocyte-chemoattractant protein-3 (MCP-3), monocyte-chemoattractant protein-1, (MIP-1,) and monocyte-chemoattractant protein-1, (MIP-1,) were detected in low concentrations. This study identified a subset of proteins present in the DKmix-conditioned medium that act as paracrine modulators of tissue repair. Moreover, it suggests that DKmix-derived conditioned medium might have therapeutic potency by promoting tissue regeneration. Copyright © 2010 John Wiley & Sons, Ltd. [source] Increased macrophage inflammatory protein-1, and -1, in BAL fluid of bronchiolitis obliterans organizing pneumoniaRESPIROLOGY, Issue 4 2003Toru ASANO Objective: CC chemokines are mainly chemotactic for monocytes and lymphocytes. The aim of this study was to evaluate the involvement of the CC chemokines, macrophage inflammatory protein (MIP)-1, and MIP-1,, in the pathogenesis of bronchiolitis obliterans organizing pneumonia (BOOP). Methodology: The concentrations of MIP-1, and MIP-1, in BAL fluid (BALF) obtained from patients with BOOP (n = 13) and control patients (CP, n= 18) were measured by enzyme-linked immunosorbent assay. Results: MIP-1, in BALF was significantly higher in patients with BOOP (mean ± SD; 123.8 ± 98.0 pg/mL) than in CP (62.5 ± 46.1 pg/mL). Significantly higher MIP-1, was also detected in patients with BOOP (51.6 ± 72.5 pg/mL) than in CP (6.4 ± 3.7 pg/mL). The concentration of MIP-1, significantly correlated with the percentage of lymphocytes in BALF, and the concentration of MIP-1, significantly correlated with the numbers of lymphocytes, neutrophils and eosinophils in BALF. Both MIP-1, and MIP-1, in BALF were decreased after corticosteroid therapy and this was accompanied by decreased lymphocytes in BALF. Conclusion: This study suggests that MIP-1, and MIP-1, may play important roles in the recruitment of immuno-inflammatory cells into the lungs, and may contribute to the pathogenesis of BOOP. [source] ORIGINAL ARTICLE: Multiple Cytokine Profile in Plasma and Amniotic Fluid in a Mouse Model of Pre-Term LaborAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 5 2009Qing Yang Problem, The rate of pre-term birth in the United States continues to rise despite several interventions. Induction of pro-inflammatory cytokines and chemokines has been implicated in the activation of the cascade of events resulting in pre-term labor. To date, no comprehensive panel of the cytokine profile in PTL has been published. Method of study, To address cytokine profiles in pre-term labor, levels of 19 plasma and amniotic fluid cytokines were measured using a multiplex immunoassay in an inflammation-induced murine model of pre-term labor. Results, Pro-inflammatory mediators, RANTES, KC, IL-6, and IL-12p40 were increased by 3 hr and remained high at 15 hr. Concentrations of KC, IL-6, IL-1,, and MIP-1, were increased in the amniotic fluid at 15 hr. Plasma levels of anti-inflammatory mediators IL-10 and IL-13 at 15 hr were unchanged and decreased respectively. Conclusion, These results suggest that stimulation of several pro-inflammatory cytokines occurs very early in the cascade of events and remains increased, whereas anti-inflammatory cytokines are either unchanged or decreased until the onset of delivery in an inflammation-induced mouse model of pre-term labor. [source] Brain Death Activates Donor Organs and Is Associated with a Worse I/R Injury After Liver TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 6 2007S. Weiss The majority of transplants are derived from donors who suffered from brain injury. There is evidence that brain death causes inflammatory changes in the donor. To define the impact of brain death, we evaluated the gene expression of cytokines in human brain dead and ideal living donors and compared these data to organ function following transplantation. Hepatic tissues from brain dead (n = 32) and living donors (n = 26) were collected at the time of donor laparotomy. Additional biopsies were performed before organ preservation, at the time of transplantation and one hour after reperfusion. Cytokines were assessed by real-time reverse transcriptase,polymerase chain reaction (RT,PCR) and cytometric bead array. Additionally, immunohistological analysis of tissue specimens was performed. Inflammatory cytokines including IL-6, IL-10, TNF-,, TGF-, and MIP-1, were significantly higher in brain dead donors immediately after laparotomy compared to living donors. Cellular infiltrates significantly increased in parallel to the soluble cytokines IL-6 and IL-10. Enhanced immune activation in brain dead donors was reflected by a deteriorated I/R injury proven by elevated alanin-amino-transferase (ALT), aspartat-amino-transferase (AST) and bilirubin levels, increased rates of acute rejection and primary nonfunction. Based on our clinical data, we demonstrate that brain death and the events that precede it are associated with a significant upregulation of inflammatory cytokines and lead to a worse ischemia/reperfusion injury after transplantation. [source] Recruitment of CXCR3+ and CCR5+ T Cells and Production of Interferon-,-Inducible Chemokines in Rejecting Human ArteriesAMERICAN JOURNAL OF TRANSPLANTATION, Issue 6 2005William R. Burns Chemokine receptors preferentially expressed by Th1 cells and their IFN-,-inducible ligands predominate in experimental and clinical allograft rejection. Previous chemokine-related transplantation studies have focused on parenchymal and microvascular inflammation which are of importance in acute rejection, but are not necessarily relevant in immune-mediated injury of conduit arteries. We have recently described a model of progressive human T cell-mediated infiltration and injury of allogeneic coronary artery segments using immunodeficient mouse hosts. In the present study, we investigated if recruitment of allogeneic T cells to different vascular compartments correlated with the expression of chemokines and their receptors. Transcripts were quantified by laser capture microdissection/real-time RT-PCR and their distribution was correlated to the corresponding protein expression detected by immunohistochemistry. Infiltrating T cells, confined to the adventitia and intima, expressed CXCR3 and CCR5, but were not recruited into the media despite production by vascular smooth muscle cells of IP-10, Mig, I-TAC, RANTES and MIP-1,. Chemokine mRNA was detected primarily in vascular cells, although chemokine protein largely localized to infiltrating leukocytes which uniquely expressed their cognate receptors. These data explain the recruitment of IFN-,-secreting T cells to the vessel wall, and reinforce the suggestion that the arterial media may be a site of immunological privilege. [source] CXC and CC chemokines induced in human renal epithelial cells by inflammatory cytokinesAPMIS, Issue 7 2009ELISKA THORBURN (NEE KRASNA) Human renal epithelial cells might play an important role during the allograft rejection by producing chemokines in response to proinflammatory cytokines such as tumor necrosis factor (TNF)-, and interleukin (IL)-1, produced by endothelial and epithelial cells early after transplantation. The production of chemokines allows inflammatory cells to be drawn into the kidney graft and therefore plays a critical role in the pathophysiologic processes that lead to the rejection of renal transplant. In this process, two chemokine superfamilies, the CC and the CXC chemokines, are the most important. The CC chemokines target mainly monocytes and T lymphocytes, while most of the CXC chemokines attract neutrophils. We showed in our study that in vitro, in unstimulated cells, basal mRNA expression of CXC chemokines (Gro,, Gro,, Gro,, ENA-78 and GCP-2, IL-8) that attract neutrophils was detectable and expression of these genes and chemokine release were increased in TNF-,- and IL-1,-induced renal epithelial cells. Most of the CC chemokines [monocyte chemotactic protein-1 (MCP-1), macrophage Inflammatory protein 1 beta (MIP-1,), regulated upon activation, normal T cell expressed and secreted (RANTES) and macrophage inflammatory protein (MIP-3,)] showed detectable mRNA expression only after stimulation with proinflammatory cytokines and not in control cells. TNF-, seems to induce preferably the expression of RANTES, MCP-1, interferon-inducible protein (IP-10) and Interferon-Inducible T-cell Alpha Chemoattractant (I-TAC), while IL-1, induces mainly IL-8 and epithelial neutrophil-activating peptide 78 (ENA-78). [source] Role of osteopontin in induction of monocyte chemoattractant protein 1 and macrophage inflammatory protein 1, through the NF-,B and MAPK pathways in rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 7 2009Wenxin Zheng Objective Osteopontin (OPN) is a proinflammatory protein with a critical role in leukocyte migration. Although OPN has been implicated in rheumatoid arthritis (RA), its underlying mechanism remains unknown. In this study, we investigated the role and molecular mechanism of OPN in the induction of 2 key chemokines, monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein 1, (MIP-1,), in RA. Methods Enzyme-linked immunosorbent assay and quantitative polymerase chain reaction were used to determine chemokine expression. Leukocyte migration in the presence of OPN was measured by chemotaxis assay. Signaling and molecular events were analyzed by immunoblotting and chromatin immunoprecipitation. Results The effect of OPN on inflammatory cell migration was mediated through its unique property of inducing the expression of MCP-1 and MIP-1, in CD14+ monocytes. The concentration of OPN was significantly elevated in RA patients and appeared to correlate with the serum levels of inflammation markers and increased expression of MCP-1 or MIP-1, in monocytes in RA patients. Endogenous production of OPN in RA synovial fluid was attributable to increased production of MCP-1 or MIP-1,, and this effect could be blocked by an anti-OPN antibody. Furthermore, the structural motif responsible for this property resided within residues 50,83 of human OPN, sparing the known RGD or SVVYGLR sequences. It was evident that the effect of OPN on chemokine expression was mediated through both the NF-,B and MAPK pathways, involving the activation of IKK,, p38, and JNK. Conclusion These results support a unique role of OPN in leukocyte migration, in the context of perpetuation of rheumatoid synovitis through the induction of MCP-1 and MIP-1,. [source] Serum chemokine profile in patients with bullous pemphigoidBRITISH JOURNAL OF DERMATOLOGY, Issue 3 2007H. Nakashima Summary Background, Bullous pemphigoid (BP) is an autoimmune inflammatory disease causing blister formation at the dermoepidermal junction. Cutaneous infiltration of activated CD4+ T cells and eosinophils is an early event in blister formation during the disease process, suggesting that the trafficking of circulating leucocytes through the sites of inflammation is crucial in the pathogenesis of the disease. While the accumulated evidence suggests that some cytokines are involved in the pathogenesis, there have been few reports about serum chemokine profiles in patients with BP. Objectives, To determine serum profiles of various chemokines and their clinical association in patients with BP. Methods, Concentrations of 10 chemokines , interferon (IFN)- , -inducible protein-10 (IP-10), monokine induced by IFN- , (MIG), macrophage inflammatory protein (MIP)-1,, MIP-1,, RANTES, eotaxin, monocyte chemoattractant protein (MCP)-1, MCP-2, MCP-3 and growth-regulated oncogene- ,, were measured in serum samples from 38 patients with BP, 16 with pemphigus vulgaris (PV) and 17 normal controls using a sandwich immunoassay-based multiplex protein array system. Results, While there was no significant increase in any serum chemokine levels in patients with PV, serum levels of IP-10 and MCP-1 were significantly increased in patients with BP compared with healthy controls. Furthermore, serum levels of IP-10, MIG, MCP-1 and eotaxin in patients with BP increased significantly with disease severity as determined by the area affected. Conclusions, These observations suggest that an elaborately orchestrated network of chemokines, especially MCP-1 and IP-10, contributes to the pathomechanism of BP. [source] Targeting MEK1/2 blocks osteoclast differentiation, function and cytokine secretion in multiple myelomaBRITISH JOURNAL OF HAEMATOLOGY, Issue 1 2007Iris Breitkreutz Summary Osteolytic bone disease in multiple myeloma (MM) is associated with upregulation of osteoclast (OCL) activity and constitutive inhibition of osteoblast function. The extracellular signal-regulated kinase 1/2 (ERK1/2) pathway mediates OCL differentiation and maturation. We hypothesized that inhibition of ERK1/2 could prevent OCL differentiation and downregulate OCL function. It was found that AZD6244, a mitogen-activated or extracellular signal-regulated protein kinase (MEK) inhibitor, blocked OCL differentiation and formation in a dose-dependent manner, evidenced by decreased ,V,3-integrin expression and tartrate-resistant acid phosphatase positive (TRAP+) cells. Functional dentine disc cultures showed inhibition of OCL-induced bone resorption by AZD6244. Major MM growth and survival factors produced by OCLs including B-cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL), as well as macrophage inflammatory protein (MIP-1,), which mediates OCL differentiation and MM, were also significantly inhibited by AZD6244. In addition to ERK inhibition, NFATc1 (nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1) and c-fos were both downregulated, suggesting that AZD6244 targets a later stage of OCL differentiation. These results indicate that AZD6244 inhibits OCL differentiation, formation and bone resorption, thereby abrogating paracrine MM cell survival in the bone marrow microenvironment. The present study therefore provides a preclinical rationale for the evaluation of AZD6244 as a potential new therapy for patients with MM. [source] Serotonin decreases HIV-1 replication in primary cultures of human macrophages through 5-HT1A receptorsBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2008B Manéglier Background and purpose: 5-HT (serotonin) is known to be involved in neuroinflammation and immunoregulation. The human immunodeficiency virus (HIV) targets cells such as monocytes/macrophages, which colocalize with 5-HT-releasing cell types, mostly platelets. In this study, we investigated the effects of 5-HT on HIV-1-infected macrophages in vitro. Experimental approach: Human macrophages cultured in serum-free medium were treated over 7 days with 5-HT at three concentrations (0.01, 1 and 100 ,M) with or without agonists and antagonists of 5-HT1A and 5-HT2 receptors. After 7 days of treatment, macrophages were infected with HIV-1/Ba-L and virus replication was monitored over 16 days and expression of proviral HIV DNA was investigated by PCR after 24 h of infection. Cell surface expression of HIV-1/Ba-L receptor (CD4) and coreceptor (CCR5) was investigated by flow cytometry. The CCR5 ligand, macrophage inflammatory protein-1, (MIP-1,), was quantified by ELISA in cell culture supernatants and MIP-1, mRNA expression was assessed by reverse transcriptase-PCR. Key results:In vitro, 5-HT downregulated the membranous expression of CCR5 and led to a decrease of HIV-1 infection, probably through its action on 5-HT1A receptors. 5-HT (100 ,M) was also able to induce overexpression of MIP-1, mRNA leading to an increase of MIP-1, secretion by human macrophages. Conclusions and implications: The effects of 5-HT on HIV infection could be a consequence of the increase in MIP-1, concentrations and/or CCR5 receptor downregulation. These results suggest that 5-HT can inhibit the replication of HIV-1 in primary culture of human macrophages through its action on 5-HT1A receptors. [source] Receptor activator of NF-,B ligand, macrophage inflammatory protein-1,, and the proteasomeCANCER, Issue S3 2003Novel therapeutic targets in myeloma Abstract BACKGROUND The bone destruction in myeloma patients is largely responsible for the clinical features of the disease. However, only recently has attention focused on identifying and developing drugs targeted specifically at the osteolysis. Receptor activator of NF-,B ligand (RANKL), macrophage inflammatory protein (MIP)-1,, and proteasomal function have been implicated in the pathogenesis of myeloma and associated bone disease. We provide "proof of principle" in preclinical myeloma models that these are indeed valid molecular targets in development of novel therapeutics. METHODS The efficacy of antagonists of RANKL and MIP-1, bioactivities (RANK.Fc and neutralizing monoclonal anti-MIP-1, antibody) in ameliorating osteolysis and reducing tumor burden was evaluated in a mouse model in which murine myeloma 5TGM1 cells are injected intravenously into syngeneic mice. In addition, the activity of a petidyl aldehyde proteasome inhibitor (proteasome inhibitor-1 [PSI]) on tumor growth was tested in a murine 5TGM1 plasmacytoma model and in mice intravenously inoculated with 5TGM1 cells. RESULTS RANK.Fc and anti-MIP-1, antibody inhibited the development and progression of osteolytic lesions and significantly reduced tumor load assessed by serum monoclonal paraprotein titers. Intratumoral injections of PSI inhibited growth of 5TGM1 plasmacytomas and induced tumor regression in some cases. In addition, systemic administration of PSI significantly prolonged time to onset of paraplegia in tumor-bearing mice. CONCLUSIONS The results highlight the critical roles of RANKL and MIP-1, in the development and progression of myeloma and provide a basis for future evaluation in myeloma patients of novel therapeutics that disrupt interactions of RANKL and MIP-1, with their cognate receptors. The data also suggest that further studies in preclincal myeloma models aimed at identifying other proteasome inhibitors with antitumor efficacy would be worthwhile. Cancer 2003;97(3 Suppl):813,7. © 2003 American Cancer Society. DOI 10.1002/cncr.11133 [source] | |||||||||||||||||||||||||||||||