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- Gidlöf, Andreas C., et al.
(författare)
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Increased retinoid signaling in vascular smooth muscle cells by proinflammatory cytokines
- 2001
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 286:2, s. 336-342
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Tidskriftsartikel (refereegranskat)abstract
- Retinoids have been shown to modulate inflammation and the immune response in many cell types including macrophages, endothelial cells, and vascular smooth muscle cells. However, present knowledge of whether inflammatory mediators modulate vitamin A status in these cells is limited. To identify the role of inflammation on retinoid metabolism in vascular smooth muscle cells, the cells were exposed to a combination of proinflammatory cytokines: interleukin-1beta, interferon-gamma, and lipopolysaccharides. Without stimulation with proinflammatory cytokines, vascular smooth muscle cells expressed retinol dehydrogenases-2 and 5 mRNA detected by RT-PCR. Stimulation with the combination of cytokines induced a substantial increase of retinol dehydrogenase-5 mRNA. This was associated with increased production of ligands for retinoic acid receptors, when assayed in a retinoic acid receptor-dependent luciferase reporter system. Our results demonstrate that inflammatory mediators activate the retinoid metabolic pathway in vascular smooth muscle cells, which potentially may modulate the inflammatory response in the vascular wall.
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| 4. |
- Karlsson, Teresa, et al.
(författare)
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Topical retinoic acid alters the expression of cellular retinoic acid-binding protein-I and cellular retinoic acid-binding protein-II in non-lesional but not lesional psoriatic skin
- 2002
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Ingår i: Experimental dermatology. - : Wiley. - 0906-6705 .- 1600-0625. ; 11:2, s. 143-152
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Tidskriftsartikel (refereegranskat)abstract
- Therapeutic retinoids have profound effects on psoriatic skin pathology but their interactions with various retinoid-binding proteins in lesional vs non-lesional skin have not been investigated. Using quantitative real-time PCR the mRNA expression of cellular retinol-binding protein I (CRBPI) and retinoic acid-binding protein I/II (CRABPI/CRABPII) was studied in psoriatic and healthy control (=normal) skin after 4 days of occlusive RA/vehicle treatment (n=6). Untreated psoriatic lesions showed a markedly elevated CRABPII/CRABPI ratio, while the CRBPI level was reduced in lesional and non-lesional skin as compared to normal skin. In RA-treated normal and non-lesional skin, the mRNA expression of CRBPI was unaltered while that of CRABPI and CRABPII was reduced by approximately 80% and increased approximately 5-fold, respectively, as compared to vehicle-treated skin. In contrast, lesional skin exposed to RA showed an almost 90% increase in CRBPI transcripts but unaltered expression of CRABPI and CRABPII, yet, the mRNA expression of several inflammatory mediators, e.g. inducible nitric oxide synthase, interferon-gamma and interleukin-1beta, was clearly reduced. Immunohistochemistry localized CRABPII to suprabasal keratinocytes in normal skin and revealed markedly elevated levels in lesional skin. RA treatment induced CRABPII protein expression in normal and non-lesional skin, to similar levels as in untreated lesions. The results indicate that the effects of RA differ in normal/non-lesional psoriatic skin and lesional skin. Whether the high expression of CRABPII in psoriatic skin lesions is due to increased amounts of endogenous retinoids in lesional skin or reflects an abnormal regulation of the CRABPII gene in psoriasis remains to be studied.
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- Sirsjö, Allan, et al.
(författare)
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Deficiency of nitric oxide synthase 2 results in increased neointima formation in a mouse model of vascular injury
- 2003
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Ingår i: Journal of Cardiovascular Pharmacology. - : Lippincott Williams & Wilkins. - 0160-2446 .- 1533-4023. ; 41:6, s. 897-902
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Tidskriftsartikel (refereegranskat)abstract
- Restenosis frequently occurs after arterial interventions. The inducible form of nitric oxide synthase (NOS2) may both promote and inhibit neointima formation. This study investigated the role of NOS2 for neointima formation in a mouse model of carotid artery injury. The common carotid artery was ligated in anesthetized mice. Homozygous NOS2 knockout mice were compared with wild-type B6/129 mice or wild-type mice treated with the pharmacologic NOS2 inhibitor aminoguanidine given orally daily after ligation (n = 6-8 in each group). Vessels were harvested for quantification of lesion size 4 weeks later, or serially after ligation for tissue analysis. mRNA for NOS2 increased 1-4 days after ligation of the carotid artery. Cell proliferation could be visualized with an antibody against proliferating cell nuclear antigen. An intimal smooth muscle cell layer, confirmed by an alpha-actin antibody, was observed in the lumen 4 weeks after injury. Inhibition of NOS2 by either pharmacologic or genetic approaches tended to increase the area of intima formation (P = 0.13 or P less than 0.05, respectively) and increased the intima/media ratio (P = 0.14 and P less than 0.01, respectively). Inhibition of NOS2 by two different approaches increased neointima formation in a mouse model of mechanical vessel injury, indicating that the NOS2 expressed in the injured vessel wall is beneficial.
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| 6. |
- Sirsjö, Allan, et al.
(författare)
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Retinoic Acid Inhibits Nitric Oxide Synthase-2 Expression through the Retinoic Acid Receptor-alpha
- 2000
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 270:3, s. 846-851
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Tidskriftsartikel (refereegranskat)abstract
- Retinoids are multipotent modulators of cellular functions and suppress cytokine-induced production of nitric oxide (NO) in several cell types. We have explored the mechanisms by which retinoic acid (RA) regulates NO production in rat aortic smooth muscle cells (VSMC), which express NOS2 in response to proinflammatory cytokines. RA inhibited interleukin-1beta (IL-1beta)-induced NOS2 mRNA expression and NO production. These effects were attenuated by the retinoic acid receptor (RAR) antagonist CD3106, indicating that they were mediated through retinoic acid receptors (RARs). The synthetic retinoid agonists CD336 (which specifically binds RARalpha) and CD367 (which binds all RARs) but not agonists specific for RARbeta, RARgamma, or RXRs reduced IL-1beta-induced NOS2 expression and NO production. When transfecting VSMC with a 1570-bp NOS2 promoter fragment fused to a luciferase reporter gene, the NOS2 promoter activity was inhibited by RA. These results indicate that retinoids modulate NO production in VSMC via RARalpha, which inhibits the transcription of the NOS2 gene.
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| 7. |
- Wuttge, Dirk M., et al.
(författare)
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CXCL16/SR-PSOX is an interferon-gamma-regulated chemokine and scavenger receptor expressed in atherosclerotic lesions
- 2004
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : American Heart Association. - 1079-5642 .- 1524-4636. ; 24:4, s. 750-755
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Atherosclerosis is an inflammatory disease. Several chemokines are important for monocyte/macrophage and T-cell recruitment to the lesion. CXCL16 is a recently discovered chemokine that is expressed in soluble and transmembrane forms, ligates CXCR6 chemokine receptor, and guides migration of activated Th1 and Tc1 cells. It is identical to scavenger receptor SR-PSOX, which mediates uptake of oxidized low-density lipoprotein. We investigated whether CXCL16 expression is controlled by interferon-gamma (IFN-gamma)-cytokine abundant in atherosclerotic lesions. METHODS AND RESULTS: CXCL16 and CXCR6 expression was identified by polymerase chain reaction and histochemistry in atherosclerotic lesions from humans and apolipoprotein-E-deficient mice. In vitro IFN-gamma induced CXCL16 in human monocytic THP-1 cells and primary human monocytes, which led to increased uptake of oxidized low-density lipoprotein in THP-1 cells, which could be blocked by peptide antibodies against CXCL16. In vivo IFN-gamma induced CXCL16 expression in murine atherosclerotic lesions. CONCLUSIONS: We demonstrate a novel role of IFN-gamma in foam cell formation through upregulation of CXCL16/SR-PSOX. CXCR6 expression in the plaque confirms the presence of cells able to respond to CXCL16. Therefore, this chemokine/scavenger receptor could serve as a molecular link between lipid metabolism and immune activity in the atherosclerotic lesion.
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| 8. |
- Wuttge, Dirk M., et al.
(författare)
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Induction of CD36 by all-trans retionic acid : retinoic acid receptor signaling in the pathogenesis of atherosclerosis
- 2001
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Ingår i: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 15:7, s. 1221-3
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Tidskriftsartikel (refereegranskat)abstract
- Scavenger receptors mediating the uptake of oxidized low-density lipoproteins (oxLDL) by macrophages play a crucial role in foam cell formation during atherosclerosis. One member of this receptor family, the thrombospondin receptor CD36, has recently been shown to mediate a major part of the oxLDL-induced aggravation of atherosclerotic lesions. Here, we show that the expression of CD36 protein and mRNA in human monocytic THP-1 cells is increased by alltrans retinoic acid (atRA), a derivative of the essential Vitamin A, which leads to increased uptake of oxLDL. CD3106, a specific antagonist at the retinoic acid receptor (RAR), inhibited the atRA-induced CD36 expression, whereas the RAR-specific agonist CD367 induced CD36 to the same degree as atRA. This indicates an RAR-mediated CD36 induction. AtRA and oxLDL had synergistic effects in up-regulating CD36 when in both THP-1 cells and primary monocytes. Applying a sensitive RAR-GAL-4 reporter assay, we could demonstrate RAR ligands in human atherosclerotic lesions. In addition, immunohistochemistry showed RAR- which indicates that atRA may contribute to foam cell formation and the progress of atherosclerosis.
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| 9. |
- Wågsäter, Dick, et al.
(författare)
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Analysis of MICA gene transcripts in human rectal cancers
- 2003
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Ingår i: Anticancer Research. - : International Institute of Anticancer Research (IIAR). - 0250-7005 .- 1791-7530. ; 23:3B, s. 2525-2529
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 10. |
- Wågsäter, Dick, et al.
(författare)
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Down-regulation of ID2 by all-trans retinoic acid in monocytic leukemia cells (THP-1)
- 2003
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Ingår i: Journal of Experimental & Clinical Cancer Research. - : BioMed Central (BMC). - 1756-9966. ; 22:3, s. 471-475
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Tidskriftsartikel (refereegranskat)abstract
- Accumulated evidence supports that both Id helix-loop-helix proteins and derivatives of vitamin A, retinoids, play a pivotal role in the regulation of cell growth and differentiation. We analyzed the effects of all-trans retinoic acid (atRA) on the gene and protein expression of Id2 in THP-1 cells and found a suppression of the levels of Id2. The down-regulation was abolished towards a constitutively expressed level of Id2 mRNA. The decreased level of Id2 was associated with growth suppression and does support the prevalent conception of the action of Id2 as a stimulator of cell growth.
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