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| 2. |
- Karaghiosoff, M, et al.
(författare)
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Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shock
- 2003
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Ingår i: Nature Immunology. - : Springer Science and Business Media LLC. - 1529-2908 .- 1529-2916. ; 4:5, s. 471-477
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Tidskriftsartikel (refereegranskat)abstract
- Toll-like receptor-4 activation by lipopolysaccharide (LPS) induces the expression of interferon-P (IFN-beta) in a MyD88-independent manner. Here we report that mice devoid of the JAK protein tyrosine kinase family member, Tyk2, were resistant to shock induced by high doses of LPS. Basal and LPS-induced expression of IFN-beta and IFN-alpha4 mRNA in Tyk2-null macrophages were diminished. However, Tyk2-null mice showed normal systemic production of nitric oxide and proinflammatory cytokines and the in vivo response to tumor necrosis factor (TNF) was unperturbed. IFN-beta-null but not STAT1-null mice were also resistant to high dose LPS treatment. Together, these data suggest that Tyk2 and IFN-beta are essential effectors in LPS induced lethality.
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| 3. |
- Aranburu, A., et al.
(författare)
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Transcription factor AP-4 is a ligand for immunoglobulin-κ promoter E-box elements
- 2001
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Ingår i: Biochemical Journal. - 0264-6021. ; 354:2, s. 431-438
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Tidskriftsartikel (refereegranskat)abstract
- Immunoglobulin (Ig)-κ promoters from humans and mice share conserved sequences. The octamer element is common to all Ig promoters and pivotal for their function. However, other conserved sequence motifs, that differ between lg variable gene families, are required for normal promoter function. These conserved motifs do not stimulate transcription in the absence of an octamer. One example is an E-box of the E47/E12 type (5′-CAGCTG-3′), which is found in all promoters of the human and murine Ig-κ gene subgroups/families, with the exception of subgroups II and VI and their related murine families. In the present study we show that the ubiquitously expressed transcription factor AP-4, and not E47, interacts specifically with the κ promoter E-boxes when tested in electrophoretic mobility-shift assays using nuclear extracts derived from human and murine B-cell lines. Furthermore, AP-4, unlike E47, did not act as a transactivator, which is in agreement with previous studies on intact κ promoters, showing that transcription is absent when the octamer element has been mutated. Based on these data, and the conservation of the 5′-CAGCTG-3′ motif among human and murine κ promoters, we propose that AP-4 is the major ligand for Ig-κ promoter E-boxes.
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| 6. |
- Isaacs, John T, et al.
(författare)
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Anti-cancer potency of tasquinimod is enhanced via albumin-binding facilitating increased uptake in the tumor microenvironment.
- 2014
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Ingår i: Oncotarget. - 1949-2553. ; 5:18, s. 8093-8106
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Tidskriftsartikel (refereegranskat)abstract
- Tasquinimod, an orally active quinoline-3-carboxamide, binds with high affinity to HDAC4 and S100A9 in cancer and infiltrating host cells within compromised tumor microenvironment inhibiting adaptive survival pathways needed for an angiogenic response. Clinical trials document that as low as 0.5-1mg tasquinimod/day is therapeutic against castrate resistant metastatic prostate cancer. Tasquinimod is metabolized via cytochrome P4503A4, but ketoconazole at a dose which completely inhibits CYP3A metabolism does not affect tasquinimod's ability to inhibit endothelial "sprouting" in vitro or anti-cancer efficacy against human prostate cancer xenografts in vivo. Tasquinimod's potency is facilitated by its reversible binding (Kd < 35 μM) to the IIA subdomain of albumin (Sudlow's site I). As blood vessels within the compromised cancer microenvironment are characterized by a higher degree of leakiness than those in normal tissues, this results in an enhanced uptake of tasquinimod bound to albumin in cancer tissue via a tumor specific process known as the "enhanced permeability and retention" (i.e., EPR) effect. Thus, despite plasma levels of < 1 µM, the EPR effect results in intracellular drug concentrations of 2-3 µM, levels several-fold higher than needed for inhibition of endothelial sprouting (IC50 ~ 0.5 µM) or for inhibition of HDAC4 and S100A9 mediated tumor growth.
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| 7. |
- Isaacs, John T., et al.
(författare)
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Tasquinimod Is an Allosteric Modulator of HDAC4 Survival Signaling within the Compromised Cancer Microenvironment
- 2013
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Ingår i: Cancer Research. - 1538-7445. ; 74:4, s. 1386-1399
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Tidskriftsartikel (refereegranskat)abstract
- Tasquinimod is an orally active antiangiogenic drug that is currently in phase III clinical trials for the treatment of castration-resistant prostate cancer. However, the target of this drug has remained unclear. In this study, we applied diverse strategies to identify the histone deacetylase HDAC4 as a target for the antiangiogenic activity of tasquinimod. Our comprehensive analysis revealed allosteric binding (Kd 10-30 nmol/L) to the regulatory Zn2+ binding domain of HDAC4 that locks the protein in a conformation preventing HDAC4/N-CoR/HDAC3 complex formation. This binding inhibited colocalization of N-CoR/HDAC3, thereby inhibiting deacetylation of histones and HDAC4 client transcription factors, such as HIF-1 alpha, which are bound at promoter/enhancers where epigenetic reprogramming is required for cancer cell survival and angiogenic response. Through this mechanism, tasquinimod is effective as a monotherapeutic agent against human prostate, breast, bladder, and colon tumor xenografts, where its efficacy could be further enhanced in combination with a targeted thapsigargin prodrug (G202) that selectively kills tumor endothelial cells. Together, our findings define a mechanism of action of tasquinimod and offer a perspective on how its clinical activity might be leveraged in combination with other drugs that target the tumor microenvironment. Cancer Res; 73(4); 1386-99. (C) 2012 AACR.
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| 8. |
- Källberg, Eva, et al.
(författare)
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Analysis of somatic mutation activity in multiple V kappa genes involved in the response to 2-phenyl-5-oxazolone
- 1993
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Ingår i: International Immunology. - : Oxford University Press (OUP). - 0953-8178 .- 1460-2377. ; 5:6, s. 81-573
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Tidskriftsartikel (refereegranskat)abstract
- We have studied somatic mutation activity early in a response to 2-phenyl-5-oxazolone coupled to ovalbumin (phOx-OVA). Although the V kappa Ox1 gene rearranged to J kappa 5 is known to predominate in this response, other closely related V kappa genes are involved. We compared the introduction of point mutations into V kappa Ox1 genes and into a set of related V kappa genes rearranged to the same J kappa segment at two time points after primary immunization. The result showed that quantitation of mutations in a single rearrangement substrate leads to an underestimation of the total mutational activity. There is pronounced somatic mutation activity early within genes that may be absent later in the response. We also show that multiple somatic mutations can be detected in B cells from draining lymph nodes after foot-pad injection with phOx-OVA already at day 7 after immunization. The data suggest a system in which mutation acts early in the response on a wide range of substrates and that selection and expansion of high affinity paratopes occurs later.
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| 9. |
- Källberg, E, et al.
(författare)
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Cell-cycle kinetics of proliferating mouse B lymphocytes in vitro
- 1995
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 41:1, s. 98-101
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Tidskriftsartikel (refereegranskat)abstract
- Resting mouse B lymphocytes were stimulated in vitro with lipopolysaccharide, Sepharose-coupled anti-kappa antibodies or a combination of the two. B lymphocytes stimulated with anti-kappa entered the cell-cycle with more rapid kinetics and at a higher frequency than did the corresponding cell population stimulated with lipopolysaccharide. Using cell cycle analysis after DNA staining combined with an M phase block, the cell-cycle kinetics of in vitro cultured B-lymphocytes was studied. The labelling index of lipopolysaccharide stimulated B lymphocytes was 60% while that for anti-kappa Sepharose stimulated cells was 85%. The generation time of the actively cycling population from both types of cultures was constant and was of the order of 18 h. Thus, the fraction of B lymphocytes induced to proliferate in vitro varies depending on the stimulus, while the growth kinetics of the actively proliferating populations are remarkably constant.
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| 10. |
- Källberg, E, et al.
(författare)
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Kinetics of somatic mutation in lymph node germinal centres
- 1994
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 40:5, s. 80-469
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Tidskriftsartikel (refereegranskat)abstract
- Somatic mutation activity in immunoglobulin V kappa genes during the response to the hapten 2-phenyl-5-oxazolone was measured in lymph node B-cell populations at various timepoints after footpad immunization. When the V kappa Ox1 genes rearranged to the J kappa 5 segment were amplified from genomic DNA using the polymerase chain reaction and sequenced, somatic mutations could be detected as early as day 4 after immunization. Somatic mutations were also detected after sequencing RNA from oxazolone-specific hybridomas derived from lymph node cells at day 4 after immunization. These early mutations were found mostly in cells with a germinal centre phenotype. No indication of selection at the population level by apoptosis was detected until day 7 after immunization. These results suggest somatic mutations can be induced very early during the immune response in lymph node cells, prior to the peak of clonal expansion and selection with regard to antigen binding.
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