| 1. |
- Kelkka, Tiina, et al.
(författare)
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Mice Lacking NCF1 Exhibit Reduced Growth of Implanted Melanoma and Carcinoma Tumors
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:12, s. e84148-
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Tidskriftsartikel (refereegranskat)abstract
- The NADPH oxidase 2 (NOX2) complex is a professional producer of reactive oxygen species (ROS) and is mainly expressed in phagocytes. While the activity of the NOX2 complex is essential for immunity against pathogens and protection against autoimmunity, its role in the development of malignant tumors remains unclear. We compared wild type and Ncf1(m1J) mutated mice, which lack functional NOX2 complex, in four different tumor models. Ncf1(m1J) mutated mice developed significantly smaller tumors in two melanoma models in which B16 melanoma cells expressing a hematopoietic growth factor FLT3L or luciferase reporter were used. Ncf1(m1J) mutated mice developed significantly fewer Lewis Lung Carcinoma (LLC) tumors, but the tumors that did develop, grew at a pace that was similar to the wild type mice. In the spontaneously arising prostate carcinoma model (TRAMP), tumor growth was not affected. The lack of ROS-mediated protection against tumor growth was associated with increased production of immunity-associated cytokines. A significant increase in Th2 associated cytokines was observed in the LLC model. Our present data show that ROS regulate rejection of the antigenic B16-luc and LLC tumors, whereas the data do not support a role for ROS in growth of intrinsically generated tumors.
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| 2. |
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| 3. |
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| 4. |
- Bemark, Mats, et al.
(författare)
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Conserved sequence elements in K promoters from mice and humans : Implications for transcriptional regulation and repertoire expression
- 1998
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Ingår i: Immunogenetics. - : Springer Science and Business Media LLC. - 0093-7711 .- 1432-1211. ; 47:3, s. 183-195
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Tidskriftsartikel (refereegranskat)abstract
- Promoter region sequences of human and mouse Igk-V genes were aligned and found to be conserved for about 200-300 base pairs (bp) within subgroups/families. No promoter similarity was found between IGKV promoters from different human subgroups. Related mouse Igk-V gene families were conserved in the promoter region but no similarity was evident when promoters from unrelated Igk-V gene families were compared. Most of the human IGKV promoter subgroups were shown to have mouse counterparts with a similarity region that extended about 150 bp upstream of the translational start codon. All promoters contained an octamer sequence element. The consensus octamer/decamer sequence was favored but only seven residues within the octamer element were strictly conserved. Furthermore, there was also sequence conservation immediately 3' of the octamer where either an A or a G residue was conserved. In addition, other DNA elements were also conserved both within the Igk-V subgroups/families and between mouse and human promoters from related subgroups/families. In several of the subgroups/families an E box of the E2A type was conserved 5' of the octamer and a CCCT element was conserved within the IGKV subgroup II and its related mouse Igk-V families. We conclude from this study that conservation of additional sequence elements besides the octamer is a common feature in Igk-V promoters but that distinct elements are conserved only within a given subgroup/family. Thus, the conservation appears to have operated at the level of function rather than at the level of recognition sequence for defined transcription factors.
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| 5. |
- Bemark, Mats, et al.
(författare)
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Diverse transcription factors are involved in the quantitative regulation of transcriptional activation of κ promoters
- 1997
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Ingår i: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 27:6, s. 1308-1318
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Tidskriftsartikel (refereegranskat)abstract
- Immunoglobulin κ promoters show sequence divergence but conserved function between different subgroups. Here we show that three separate 5' elements are required for synergistic stimulation of transcription with the decamer in a κ promoter. These sites are a 5' E-box, a 3' AT-rich region in the pentadecamer (pd) element, and the κ-Y element. Elf-1 is a novel κ-Y element ligand induced upon mitogenic stimulation of resting B lymphocytes. Furthermore, the 5' E2A-like E-box in the pd element could be substituted by an upstream stimulatory factor motif with conservation of function. Thus, the synergistic activation requirements of κ transcription is strictly dependent on the quantitative presence of transcription factor-binding motifs 5' of the decamer, but these differ qualitatively in that they may bind an array of proteins with conserved function.
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| 6. |
- Bemark, Mats, et al.
(författare)
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Purification and characterization of a protein binding to the SP6 κ promoter : A potential role for CArG-box binding factor-A in κ transcription
- 1998
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Ingår i: Journal of Biological Chemistry. - : Elsevier BV. - 0021-9258. ; 273:30, s. 18881-18890
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Tidskriftsartikel (refereegranskat)abstract
- A protein interacting with an A-T-rich region that is a positive control element within the SP6 κ promoter was purified and identified as CArG-box binding factor-A. The purified protein was shown to interact specifically with the coding strand of single-stranded DNA and, with lower affinity, with double-stranded DNA. A mutation that inhibited binding of the protein to the A-T-rich region also aborted the transcriptional stimulatory effect of the region. Two Ets proteins, PU.1 and elf-1, that have previously been shown to bind to an adjacent DNA element were shown to physically interact with CArG- box binding factor.A. An antiserum raised against the protein recognized two different forms indicating either that different splice-forms of CArG-box binding factor-A are expressed, or that the protein is subject to posttranslational modification.
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| 7. |
- Bemark, Mats, et al.
(författare)
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Spi-C, a novel Ets protein that is temporally regulated during B lymphocyte development
- 1999
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Ingår i: Journal of Biological Chemistry. - : Elsevier BV. - 0021-9258. ; 274:15, s. 10259-10267
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Tidskriftsartikel (refereegranskat)abstract
- A novel Ets protein was isolated by yeast one-hybrid screening of a cDNA library made from lipopolysaccharide-stimulated mouse splenic B cells, using the SP6 κ promoter κY element as a bait. The novel Ets protein was most closely related to PU.1 and Spi-B within the DNA binding Ets domain and was therefore named Spi-C. However, Spi-C may represent a novel subgroup within the Ets protein family, as it differed significantly from Spi-B and PU.1 within helix 1 of the Ets domain. Spi-C was encoded by a single-copy gene that was mapped to chromosome 10, region C. Spi-C interacted with DNA similarly to PU.1 as judged by methylation interference, band-shift and site selection analysis, and activated transcription of a κY element reporter gene upon co-transfection of HeLa cells. Spi-C RNA was expressed in mature B lymphocytes and at lower levels in macrophages. Furthermore, pre-B cell and plasma cell lines were Spi-C-negative, suggesting that Spi-C might be a regulatory molecule during a specific phase of B lymphoid development.
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| 8. |
- Bengtsson, Anders A, et al.
(författare)
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Pharmacokinetics, tolerability, and preliminary efficacy of ABR-215757, a new quinoline-3-carboxamide derivative, in murine and human SLE
- 2012
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 64:5, s. 1579-1588
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To assess the efficacy of ABR-215757, a new immunomodulatory small molecule in a murine SLE model, to evaluate the pharmacokinetics and tolerability in SLE patients at doses predicted to be efficacious and safe, and to determine the maximum tolerated dose (MTD). METHODS: The efficacy of ABR-215757 was studied in lupus prone MRLlpr/lpr mice and compared with established SLE treatments. Dose response data of ABR-215757 were together with pharmacokinetic data used to calculate effective and safe clinical doses. The pharmacokinetics and tolerance of ABR-215757 were evaluated in a Phase Ib double-blind, placebo controlled, dose-escalation study where cohorts of SLE patients received daily oral treatment for 12 weeks. RESULTS: Disease inhibition in MRLlpr/lpr mice, comparable to that of prednisolone and mycophenolate mofetil, was obtained with ABR-215757. Prominent effects on disease manifestations, serological markers and a steroid sparing effect were seen for ABR-215757. The pharmacokinetic properties in SLE patients were linear and well suitable for once daily oral treatment. The majority of the adverse events (AEs) were mild or moderate and transient. The most frequent AEs were arthralgia and myalgia, reported at the highest (4.5 and 6 mg/day) dose levels. At 4.5 mg and higher some AEs of severe intensity and serious adverse events (SAEs) were reported. CONCLUSION: ABR-215757 effectively inhibited disease and had a steroid sparing effect in experimental lupus. Clinical doses up to 3 mg/day, dose levels predicted from pre-clinical studies to be efficacious and safe, were well tolerated in the SLE patients. The MTD was concluded to be 4.5 mg/day.
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| 9. |
- Bengtsson, Anders, et al.
(författare)
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Pharmacokinetics, tolerability, and preliminary efficacy of paquinimod (ABR-215757), a new quinoline-3-carboxamide derivative: Studies in lupus-prone mice and a multicenter, randomized, double-blind, placebo-controlled, repeat-dose, dose-ranging study in patients with systemic lupus erythematosus
- 2012
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 64:5, s. 1579-1588
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Tidskriftsartikel (refereegranskat)abstract
- Objective To assess the efficacy of paquinimod, a new immunomodulatory small molecule, in a murine lupus model, and to evaluate its pharmacokinetics and tolerability in systemic lupus erythematosus (SLE) patients at doses predicted to be efficacious and safe and determine the maximum tolerated dose. Methods The efficacy of paquinimod was studied in lupus-prone MRL-lpr/lpr mice and compared with that of established SLE treatments. Dose-response data and pharmacokinetic data were used to calculate effective and safe clinical doses of paquinimod. The pharmacokinetics and tolerability of paquinimod were evaluated in a phase Ib double-blind, placebo controlled, dose-ranging study in which cohorts of SLE patients received daily oral treatment for 12 weeks. Results Paquinimod treatment resulted in disease inhibition in MRL-lpr/lpr mice, comparable to that obtained with prednisolone and mycophenolate mofetil; prominent effects on disease manifestations and serologic markers and a steroid-sparing effect were observed. In patients with SLE, the pharmacokinetic properties of paquinimod were linear and well suitable for once-daily oral treatment. The majority of the adverse events (AEs) were mild or moderate, and transient. The most frequent AEs were arthralgia and myalgia, reported with the highest dose levels of paquinimod (4.5 mg/day and 6.0 mg/day). At the 4.5 mg/day dose level and higher, some AEs of severe intensity and serious adverse events were reported. Conclusion Paquinimod effectively inhibited disease and had a steroid-sparing effect in experimental lupus. Results from preclinical models together with pharmacokinetic data were successfully translated into a safe clinical dose range, and doses of up to 3.0 mg/day were well tolerated in the SLE patients. Taken together, the promising combined data from a murine model and human SLE support the future clinical development of paquinimod.
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| 10. |
- Bennett, Matthew, et al.
(författare)
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Was it there all the time?
- 2003
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 1365-3083 .- 0300-9475. ; 57:6, s. 499-505
-
Forskningsöversikt (refereegranskat)abstract
- The complement system is old, yet it may still have something new to teach us. For many years, research has existed which shows that C3d, in addition to its established role as an adjuvant, could have an immunosuppressive activity. Being true, it suggests that a common mechanism may be used both by organisms and by their pathogens to prevent unwanted immune responses.
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| 11. |
- Bergenfelz, Caroline, et al.
(författare)
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S100A9 expressed in ER(-)PgR(-) breast cancers induces inflammatory cytokines and is associated with an impaired overall survival.
- 2015
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 113:8, s. 1234-1243
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is the most common cancer form among women today. Depending on hormone receptor status, breast cancers are divided into different subtypes with vastly varying prognosis. S100A9 is a calcium-binding protein that is associated with inflammation and expressed not only in myeloid cells but also in some tumours. The role for S100A9 in the malignant cells is not well characterised; however, previous studies have shown that the protein could have important immune-modulating properties.
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| 12. |
- Biondo, Carmelo, et al.
(författare)
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IFN-alpha/beta signaling is required for polarization of cytokine responses toward a protective type 1 pattern during experimental cryptococcosis
- 2008
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Ingår i: Journal of Immunology. - 1550-6606. ; 181:1, s. 566-573
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Tidskriftsartikel (refereegranskat)abstract
- The antiviral activities of type I IFNs have long been established. However, comparatively little is known of their role in defenses against nonviral pathogens. We examined here the effects of type I IFNs on host resistance against the model pathogenic yeast Cryptococcus neoformans. After intratracheal or i.v. challenge with this fungus, most mice lacking either the IFN-alpha/beta receptor (IFN-alpha/beta R) or IFN-beta died from unrestrained pneumonia and encephalitis, while all wild-type controls survived. The pulmonary immune response of IFN-beta/BR-/- mice was characterized by increased expression of IL-4, IL-13, and IL-10, decreased expression of TNF-alpha, IFN-gamma, inducible NO synthetase, and CXCL10, and similar levels of IL-12 mRNA, compared with wild-type controls. Histopathological analysis showed eosinophilic infiltrates in the lungs of IFN-alpha/beta(-/-) mice, although this change was less extensive than that observed in similarly infected IFN-gamma R-deficient animals. Type I IFN responses could not be detected in the lung after intratracheal challenge. However, small, but statistically significant, elevations in IFN-beta levels were measured in the supernatants of bone marrow-derived macrophages or dendritic cells infected with C neoformans. Our data demonstrate that type I IFN signaling is required for polarization of cytokine responses toward a protective type I pattern during cryptococcal infection.
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| 13. |
- Björk, Per, et al.
(författare)
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Identification of human S100A9 as a novel target for treatment of autoimmune disease via binding to quinoline-3-carboxamides.
- 2009
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Ingår i: PLoS Biology. - : Public Library of Science (PLoS). - 1545-7885. ; 7:4, s. 800-812
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Tidskriftsartikel (refereegranskat)abstract
- Despite more than 25 years of research, the molecular targets of quinoline-3-carboxamides have been elusive although these compounds are currently in Phase II and III development for treatment of autoimmune/inflammatory diseases in humans. Using photoaffinity cross-linking of a radioactively labelled quinoline-3-carboxamide compound, we could determine a direct association between human S100A9 and quinoline-3-carboxamides. This interaction was strictly dependent on both Zn++ and Ca++. We also show that S100A9 in the presence of Zn++ and Ca++ is an efficient ligand of receptor for advanced glycation end products (RAGE) and also an endogenous Toll ligand in that it shows a highly specific interaction with TLR4/MD2. Both these interactions are inhibited by quinoline-3-carboxamides. A clear structure-activity relationship (SAR) emerged with regard to the binding of quinoline-3-carboxamides to S100A9, as well as these compounds potency to inhibit interactions with RAGE or TLR4/MD2. The same SAR was observed when the compound's ability to inhibit acute experimental autoimmune encephalomyelitis in mice in vivo was analysed. Quinoline-3-carboxamides would also inhibit TNFalpha release in a S100A9-dependent model in vivo, as would antibodies raised against the quinoline-3-carboxamide-binding domain of S100A9. Thus, S100A9 appears to be a focal molecule in the control of autoimmune disease via its interactions with proinflammatory mediators. The specific binding of quinoline-3-carboxamides to S100A9 explains the immunomodulatory activity of this class of compounds and defines S100A9 as a novel target for treatment of human autoimmune diseases.
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| 14. |
- Björkman, Per, et al.
(författare)
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Common Interactions between S100A4 and S100A9 Defined by a Novel Chemical Probe.
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:5
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Tidskriftsartikel (refereegranskat)abstract
- S100A4 and S100A9 proteins have been described as playing roles in the control of tumor growth and metastasis. We show here that a chemical probe, oxyclozanide (OX), selected for inhibiting the interaction between S100A9 and the receptor for advanced glycation end-products (RAGE) interacts with both S100A9 and S100A4. Furthermore, we show that S100A9 and S100A4 interact with RAGE and TLR4; interactions that can be inhibited by OX. Hence, S100A4 and S100A9 display similar functional elements despite their primary sequence diversity. This was further confirmed by showing that S100A4 and S100A9 dimerize both in vitro and in vivo. All of these interactions required levels of Zn(++) that are found in the extracellular space but not intracellularly. Interestingly, S100A4 and S100A9 are expressed by distinct CD11b(+) subpopulations both in healthy animals and in animals with either inflammatory disease or tumor burden. The functions of S100A9 and S100A4 described in this paper, including heterodimerization, may therefore reflect S100A9 and S100A4 that are released into the extra-cellular milieu.
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| 15. |
- Carlsson, Robert, et al.
(författare)
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Genomic structure of mouse SPI-C and genomic structure and expression pattern of human SPI-C.
- 2002
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Ingår i: Gene. - 1879-0038. ; 299:1-2, s. 271-278
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Tidskriftsartikel (refereegranskat)abstract
- Erythroblast transformation-specific domain (ETS) transcription factors regulate some of the critical molecular mechanisms controlling the differentiation of multipotent haematopoietic progenitor cells into effector B-lymphocytes. The SPI-group ETS-protein transcription factors PU.1 and SPI-B play essential and, although coexpressed and binding to similar DNA sequences, unique roles in B-cell differentiation in mice. Mouse SPI-C is an SPI-group ETS protein expressed temporarily during B-cell development and in macrophages. Here we present the genomic organization of the mouse SPI-C gene, and show by rapid amplification of cDNA ends (5′-RACE) analysis that transcription of the mouse SPI-C mRNA starts at a single site producing a single processed transcript. We have also isolated a cDNA clone encoding the human SPI-C homologue, which displays 65% amino acid identity to the murine protein. In addition, we show that the genomic structure of the human and mouse genes are similar, containing a 5′ non-coding exon followed by five coding exons. Human SPI-C mRNA is preferentially detected in foetal and adult spleen, lymph nodes and at lower levels in bone marrow and foetal liver. Finally a phylogenetic prediction analysis of SPI-group protein sequences suggest that the SPI-C proteins form a distinct subgroup, with human SPI-C being closest related to the mouse SPI-C protein.
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| 16. |
- Carlsson, Robert, et al.
(författare)
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SPI-C, a PU-box binding ETS protein expressed temporarily during B-cell development and in macrophages, contains an acidic transactivation domain located to the N-terminus.
- 2003
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Ingår i: Molecular Immunology. - 1872-9142. ; 39:16, s. 1035-1043
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Tidskriftsartikel (refereegranskat)abstract
- Mice deficient for SPI-group ETS transcription factors PU.1 or SPI-B fail to generate lymphocytes or do not mount normal antibody mediated immune responses, respectively. PU.1 expression is restricted to B-, T-lymphocytes and macrophages, while SPI-B is expressed in B- and T-lymphocytes. SPI-C is an ETS transcription factor closely related to PU.1 and SPI-B, and expressed temporarily during B-cell development and in macrophages. By deletion and mutation analysis we show that the SPI-C protein has a transactivation domain located to the N-terminus, and that the transactivation activity is reduced to that of the DNA binding domain (DBD) alone when four aspartic acid residues are mutated to alanines. PU.1 and SPI-B regulate transcription from acidic domains located to the N-terminus and by recruiting the co-activator PIP to adjacent sites in a sequence specific manner. In contrast to PU.1 and PIP, SPI-C and PIP were unable to form a distinct ternary complex on the Ig λ light chain λ2–4 enhancer element, suggesting that SPI-C could act both as a positive and negative transcriptional regulator during B-lymphocyte differentiation.
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| 17. |
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| 18. |
- Chakraborty, Paramita, et al.
(författare)
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Vesicular Location and Transport of S100A8 and S100A9 Proteins in Monocytoid Cells.
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:12
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Tidskriftsartikel (refereegranskat)abstract
- We show here, by using surface biotinylation, followed by Western blotting or surface plasmon resonance analysis, that very low levels of S100A8 and/or S100A9 can be detected on the surface of THP-1 cells or freshly isolated human monocytes. This was supported by immune-electron microscopy where we observed membrane-associated expression of the proteins restricted to small patches. By using confocal microscopy we could determine that S100A8 and S100A9 protein in THP-1 cells or freshly isolated human monocytes was mostly present in vesicular structures. This finding was confirmed using immune-electron microscopy. Subcellular fractionation and confocal microscopy showed that these vesicular structures are mainly early endosomes and endolysosomes. Our subsequent studies showed that accumulation of S100A8 and S100A9 in the endolysosomal compartment is associated with induction of their release from the cells. Furthermore, an inhibitor of lysosomal activity could modulate the release of S100A8 and S100A9 in the extracellular milieu. Our current results suggest that the S100A8 and S100A9 proteins are primarily associated with certain kinds of cytosolic vesicles and may be secreted via an endolysosomal pathway.
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| 19. |
- Coulon, Severine, et al.
(författare)
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Polymeric IgA1 controls erythroblast proliferation and accelerates erythropoiesis recovery in anemia
- 2011
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 17:11, s. 163-1456
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Tidskriftsartikel (refereegranskat)abstract
- Anemia because of insufficient production of and/or response to erythropoietin (Epo) is a major complication of chronic kidney disease and cancer. The mechanisms modulating the sensitivity of erythroblasts to Epo remain poorly understood. We show that, when cultured with Epo at suboptimal concentrations, the growth and clonogenic potential of erythroblasts was rescued by transferrin receptor 1 (TfR1)-bound polymeric IgA1 (pIgA1). Under homeostatic conditions, erythroblast numbers were increased in mice expressing human IgA1 compared to control mice. Hypoxic stress of these mice led to increased amounts of pIgA1 and erythroblast expansion. Expression of human IgA1 or treatment of wild-type mice with the TfR1 ligands pIgA1 or iron-loaded transferrin (Fe-Tf) accelerated recovery from acute anemia. TfR1 engagement by either pIgA1 or Fe-Tf increased cell sensitivity to Epo by inducing activation of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways. These cellular responses were mediated through the TfR1-internalization motif, YXX Phi. Our results show that pIgA1 and TfR1 are positive regulators of erythropoiesis in both physiological and pathological situations. Targeting this pathway may provide alternate approaches to the treatment of ineffective erythropoiesis and anemia.
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| 20. |
- Deronic, Adnan, et al.
(författare)
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The anti-tumor effect of the quinoline-3-carboxamide tasquinimod : Blockade of recruitment of CD11b+ Ly6Chi cells to tumor tissue reduces tumor growth
- 2016
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous work has demonstrated immunomodulatory, anti-tumor, anti-metastatic and anti-angiogenic effects of the small molecule quinoline-3-carboxamide tasquinimod in pre-clinical cancer models. To better understand the anti-tumor effects of tasquinimod in transplantable tumor models, we have evaluated the impact of the compound both on recruitment of myeloid cells to tumor tissue and on tumor-induced myeloid cell expansion as these cells are known to promote tumor development. Methods: Mice bearing subcutaneous 4 T1 mammary carcinoma tumors were treated with tasquinimod in the drinking water. A BrdU-based flow cytometry assay was utilized to assess the impact of short-term tasquinimod treatment on myeloid cell recruitment to tumors. Additionally, long-term treatment was performed to study the anti-tumor effect of tasquinimod as well as its effects on splenic myeloid cells and their progenitors. Myeloid cell populations were also immune-depleted by in vivo antibody treatment. Results: Short-term tasquinimod treatment did not influence the proliferation of splenic Ly6Chi and Ly6Ghi cells, but instead reduced the influx of Ly6Chi cells to the tumor. Treatment with tasquinimod for various periods of time after tumor inoculation revealed that the anti-tumor effect of this compound mainly operated during the first few days of tumor growth. Similar to tasquinimod treatment, antibody-mediated depletion of Ly6Chi cells within that same time frame, caused reduced tumor growth, thereby confirming a significant role for these cells in tumor development. Additionally, long-term tasquinimod treatment reduced the splenomegaly and expansion of splenic myeloid cells during a later phase of tumor development. In this phase, tasquinimod normalized the tumor-induced alterations in myeloerythroid progenitor cells in the spleen but had only limited impact on the same populations in the bone marrow. Conclusions: Our results indicate that tasquinimod treatment reduces tumor growth by operating early after tumor inoculation and that this effect is at least partially caused by reduced recruitment of Ly6Chi cells to tumor tissue. Long-term treatment also reduces the number of splenic myeloid cells and myeloerythroid progenitors, but these effects did not influence established rapidly growing tumors.
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| 21. |
- Deronic, Adnan, et al.
(författare)
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The quinoline-3-carboxamide paquinimod (ABR-215757) reduces leukocyte recruitment during sterile inflammation: Leukocyte- and context-specific effects.
- 2014
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Ingår i: International Immunopharmacology. - : Elsevier BV. - 1878-1705 .- 1567-5769. ; 18:2, s. 290-297
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Tidskriftsartikel (refereegranskat)abstract
- Quinoline-3-carboxamides (Q-compounds) are currently in clinical development for both autoimmune disease and cancer. We have previously shown that the Q-compound paquinimod (ABR-215757) significantly ameliorates disease symptoms in several mouse models of human inflammatory disease. Considering that recruitment of inflammatory cells into tissue is a common denominator of these models, we have in this report investigated whether paquinimod would interfere with cell accumulation during sterile peritoneal inflammation. To mimic the cell recruitment elicited by tissue injury, we used necrotic cells to induce the acute inflammatory response. We show that per oral treatment with paquinimod significantly reduced the accumulation of Ly6C(hi) inflammatory monocytes and eosinophils, but not neutrophils, in this model, and that this correlated with reduced number of such cells also in the omentum. Treatment also reduced the accumulation of these cell populations at a subcutaneous site of inflammation. In alum-induced inflammation, however, neutrophils were the dominant cell population and paquinimod failed to reduce the accumulation of inflammatory cells. Taken together, our results indicate that paquinimod selectively inhibits cell recruitment during acute sterile inflammation, but that this effect is context-dependent. These data have important implications for the understanding of the mechanism of action of Q-compounds in both pre-clinical and clinical settings.
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| 22. |
- Erlandsson, Lena, et al.
(författare)
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Joining chain-expressing and -nonexpressing B cell populations in the mouse
- 2001
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 194:5, s. 557-570
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Tidskriftsartikel (refereegranskat)abstract
- The diphtheria toxin A chain (DTA) was gene targeted into the Joining chain (J chain) locus to create a mouse strain selecting against J chain-expressing cells, JDTA mice. Serum immunoglobulin (Ig)M and serum IgG were reduced six to eightfold, while serum IgA was elevated 14-fold in these mice. JDTA mice were immune competent although the serum Ig response compared with wild-type mice was reduced sixfold at day 14 but only fourfold at day 45 after immunization. Exchanging the DTA gene with a cDNA for c-myc resulted in mice with a distinct phenotype with increased Ig production and enhanced humoral immune responses. Analysis of single B cells stimulated by lipopolysaccharide in vitro using reverse transcription-polymerase chain reaction showed that J chain-nonexpressing B cells could be detected that had a secretory phenotype as determined by an abundance of transcript for secretory IgM. Finally, limiting dilution analysis of peripheral B cells showed that J chain expression was a clonal property already established in naive, peripheral B lymphocytes.
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| 23. |
- Frick, Inga-Maria, et al.
(författare)
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Uptake and intracellular transportation of a bacterial surface protein in lymphoid cells.
- 2002
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Ingår i: Molecular Microbiology. - : Wiley. - 1365-2958 .- 0950-382X. ; 44:4, s. 917-934
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Tidskriftsartikel (refereegranskat)abstract
- Some strains of the human pathogen Streptococcus pyogenes express a surface protein called protein H, which is released from the streptococcal surface by a cysteine proteinase produced by the bacteria. Here, we find that soluble protein H binds to the surface of lymphocytes and granulocytes, and that the molecule is taken up by lymphocytes and transported to the perinuclear region. The translocation over the cell membrane is rapid, and the uptake and intracellular transportation is not dependent on actin polymerization. Protein H could be immunoprecipitated from cell extracts and nuclear preparations of lymphocytes, and analysis of molecular interactions between pro-tein H and proteins of different cellular compart-ments demonstrated a binding to nucleophosmin/ B23, a protein known to shuttle between the cytoplasm and the nucleus, and to the nuclear proteins SET and hnRNP A2/B1. Nucleophosmin/B23 was co-immunoprecipitated with protein H from cell and nuclear extracts, and binding experiments, including kinetic analyses, suggest that protein H dissociating from nucleophosmin/B23 complexes in the perinuclear region or in the nucleus binds to proteins SET and hnRNP A2/B1. Finally, the uptake and intracellular transportation of protein H was found to result in a cytostatic effect on B and T lymphocytes.
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| 24. |
- Gram, Magnus, et al.
(författare)
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The radical-binding lipocalin A1M binds to a Complex I subunit and protects mitochondrial structure and function.
- 2013
-
Ingår i: Antioxidants & Redox Signaling. - : Mary Ann Liebert Inc. - 1557-7716 .- 1523-0864. ; 18:16, s. 2017-2028
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Tidskriftsartikel (refereegranskat)abstract
- Aims: During cell death, energy-consuming cell degradation and recycling programs are performed. Maintenance of energy-delivery during cell death is therefore crucial but the mechanisms to keep the mitochondrial functions intact during these processes are poorly understood. We have investigated the hypothesis that the heme- and radical-binding ubiquitous protein A1M (α1-microglobulin) is involved in protection of the mitochondria against oxidative insult during cell death. Results: Using blood cells, keratinocytes and liver cells, we show that A1M binds with high affinity to apoptosis-induced cells and is localized to mitochondria. The mitochondrial Complex I subunit NDUFAB1 was identified as a major molecular target of the A1M-binding. Furthermore, A1M was shown to inhibit the swelling of mitochondria, and to reverse the severely abrogated ATP-production of mitochondria when exposed to heme and ROS. Innovation: Import of the radical- and heme-binding protein A1M from the extracellular compartment confers protection of mitochondrial structure and function during cellular insult. Conclusion: A1M binds to a subunit of Complex I and has a role in assisting the mitochondria to maintain its energy delivery during cell death. A1M may also, at the same time, counteract and eliminate the ROS generated by the mitochondrial respiration to prevent oxidative damage to surrounding healthy tissue.
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