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- Fuchs, C. D., et al.
(författare)
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GLP-2 Improves Hepatic Inflammation and Fibrosis in Mdr2-/- Mice Via Activation of NR4a1/Nur77 in Hepatic Stellate Cells and Intestinal FXR Signaling
- 2023
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Ingår i: Cellular and Molecular Gastroenterology and Hepatology. - 2352-345X. ; 16:5, s. 847-856
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Glucagon-like peptide (GLP)-2 may exert antifibrotic effects on hepatic stellate cells (HSCs). Thus, we aimed to test whether application of the GLP-2 analogue teduglutide has hepatoprotective and antifibrotic effects in the Mdr2/Abcb4(-/-) mouse model of sclerosing cholangitis displaying hepatic inflammation and fibrosis. METHODS: Mdr2(-/-) mice were injected daily for 4 weeks with teduglutide followed by gene expression profiling (bulk liver; isolated HSCs) and immunohistochemistry. Activated HSCs (LX2 cells) and immortalized human hepatocytes and human intestinal organoids were treated with GLP-2. mRNA profiling by reverse transcription polymerase chain reaction and elec-trophoretic mobility shift assay using cytosolic and nuclear protein extracts was performed. RESULTS: Hepatic inflammation, fibrosis, and reactive chol-angiocyte phenotype were improved in GLP-2-treated Mdr2(-/-) mice. Primary HSCs isolated from Mdr2(-/-)mice and LX2 cells exposed to GLP-2 in vitro displayed significantly increased mRNA expression levels of NR4a1/Nur77 (P < .05). Electro-phoretic mobility shift assay revealed an increased nuclear NR4a1 binding after GLP-2 treatment in LX2 cells. Moreover, GLP-2 alleviated the Tgf beta-mediated reduction of NR4a1 nuclear binding activity. In vivo, GLP-2 treatment of Mdr2(-/-) mice resulted in increased intrahepatic levels of muricholic acids (accordingly Cyp2c70 mRNA expression was significantly increased), and in reduced mRNA levels of Cyp7a1 and FXR. Serum Fgf15 levels were increased in Mdr2(-/-) mice treated with GLP-2. Accordingly, GLP-2 treatment of human intestinal organoids activated their FXR-FGF19 signaling axis. CONCLUSIONS: GLP-2 treatment increased NR4a1/Nur77 activation in HSCs, subsequently attenuating their activation. GLP-2 promoted intestinal Fxr-Fgf15/19 signaling resulting in reduced Cyp7a1 and increased Cyp2c70 expression in the liver, contributing to hepatoprotective and antifibrotic effects of GLP2 in the Mdr2(-/-) mouse model.
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- Liu, GJ, et al.
(författare)
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Repression of the B cell identity factor Pax5 is not required for plasma cell development
- 2020
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 217:11
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Tidskriftsartikel (refereegranskat)abstract
- B cell and plasma cell fates are controlled by different transcriptional networks, as exemplified by the mutually exclusive expression and cross-antagonism of the B cell identity factor Pax5 and the plasma cell regulator Blimp1. It has been postulated that repression of Pax5 by Blimp1 is essential for plasma cell development. Here, we challenged this hypothesis by analyzing the IghPax5/+ mouse, which expressed a Pax5 minigene from the immunoglobulin heavy-chain locus. Despite high Pax5 expression, plasma cells efficiently developed in young IghPax5/+ mice at steady state and upon immunization, while their number moderately declined in older mice. Although Pax5 significantly deregulated the plasma cell expression program, key plasma cell regulators were normally expressed in IghPax5/+ plasma cells. While IgM and IgA secretion by IghPax5/+ plasma cells was normal, IgG secretion was modestly decreased. Hence, Pax5 repression is not essential for robust plasma cell development and antibody secretion, although it is required for optimal IgG production and accumulation of long-lived plasma cells.
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- Tschan, V. J., et al.
(författare)
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Preclinical investigations using Lu-177 Lu-lbu-DAB-PSMA toward its clinical translation for radioligand therapy of prostate cancer
- 2022
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 49, s. 3639-3650
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Tidskriftsartikel (refereegranskat)abstract
- [Lu-177]Lu-Ibu-DAB-PSMA was previously characterized with moderate albumin-binding properties enabling high tumor accumulation but reasonably low retention in the blood. The aim of this study was to investigate [Lu-177]Lu-Ibu-DAB-PSMA in preclinical in vivo experiments and compare its therapeutic efficacy and potential undesired side effects with those of [Lu-177]Lu-PSMA-617 and the previously developed [Lu-177]Lu-PSMA-ALB-56. BALB/c nude mice without tumors were investigated on Day 10 and 28 after injection of 10 MBq radioligand. It was revealed that most plasma parameters were in the same range for all groups of mice and histopathological examinations of healthy tissue did not show any alternations in treated mice as compared to untreated controls. Based on these results, a therapy study over twelve weeks was conducted with PC-3 PIP tumor-bearing mice for comparison of the radioligands's therapeutic efficacy up to an activity of 10 MBq (1 nmol) per mouse. In agreement with the increased mean absorbed tumor dose, [Lu-177]Lu-Ibu-DAB-PSMA (similar to 6.6 Gy/ MBq) was more effective to inhibit tumor growth than [Lu-177]Lu-PSMA-617 (similar to 4.5 Gy/MBq) and only moderately less potent than [Lu-177]Lu-PSMA-ALB-56 (similar to 8.1 Gy/MBq). As a result, the survival of mice treated with 2 MBq of an albumin-binding radioligand was significantly increased (p < 0.05) compared to that of mice injected with [Lu-177]Lu-PSMA-617 or untreated controls. The majority of mice treated with 5 MBq or 10 MBq [Lu-177]Lu-Ibu-DAB-PSMA or [Lu-177]Lu-PSMA-ALB-56 were still alive at study end. Hemograms of immunocompetent mice injected with 30 MBq [Lu-177]Lu-Ibu-DAB-PSMA or 30 MBq [Lu-177]Lu-PSMA-617 showed values in the same range as untreated controls. This was, however, not the case for mice treated with [Lu-177]Lu-PSMA-ALB-56 which revealed a drop in lymphocytes and hemoglobin at Day 10 and Day 28 after injection. The data of this study demonstrated a significant therapeutic advantage of [Lu-177]Lu-Ibu-DAB-PSMA over [Lu-177]Lu-PSMA-617 and a more favorable safety profile as compared to that of [Lu-177]Lu-PSMA-ALB-56. Based on these results, [Lu-177]Lu-Ibu-DAB-PSMA may has the potential for a clinical translation.
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- Rauschmeier, R, et al.
(författare)
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Bhlhe40 function in activated B and TFH cells restrains the GC reaction and prevents lymphomagenesis
- 2021
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 219:2
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Tidskriftsartikel (refereegranskat)abstract
- The generation of high-affinity antibodies against pathogens and vaccines requires the germinal center (GC) reaction, which relies on a complex interplay between specialized effector B and CD4 T lymphocytes, the GC B cells and T follicular helper (TFH) cells. Intriguingly, several positive key regulators of the GC reaction are common for both cell types. Here, we report that the transcription factor Bhlhe40 is a crucial cell-intrinsic negative regulator affecting both the B and T cell sides of the GC reaction. In activated CD4 T cells, Bhlhe40 was required to restrain proliferation, thus limiting the number of TFH cells. In B cells, Bhlhe40 executed its function in the first days after immunization by selectively restricting the generation of the earliest GC B cells but not of early memory B cells or plasmablasts. Bhlhe40-deficient mice with progressing age succumbed to a B cell lymphoma characterized by the accumulation of monoclonal GC B-like cells and polyclonal TFH cells in various tissues.
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