| 1. |
- Andersson, Sofia E M, 1979, et al.
(författare)
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Activation of Fms-like tyrosine kinase 3 signaling enhances survivin expression in a mouse model of rheumatoid arthritis.
- 2012
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 7:10
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Tidskriftsartikel (refereegranskat)abstract
- Survivin is known as an inhibitor of apoptosis and a positive regulator of cell division. We have recently identified survivin as a predictor of joint destruction in patients with rheumatoid arthritis (RA). Flt3 ligand (Flt3L) is expressed in the inflamed joints and has adjuvant properties in arthritis. Studies on 90 RA patients (median age 60.5 years [range, 24-87], disease duration 10.5 years [range, 0-35]) show a strong positive association between the levels of survivin and Flt3L in blood. Here, we present experimental evidence connecting survivin and Flt3L signaling. Treatment of BALB/c mice with Flt3L led to an increase of survivin in the bone marrow and in splenic dendritic cells. Flt3L changed the profile of survivin splice variants, increasing transcription of the short survivin40 in the bone marrow. Treatment with an Flt3 inhibitor reduced total survivin expression in bone marrow and in the dendritic cell population in spleen. Inhibition of survivin transcription in mice, by shRNA lentiviral constructs, reduced the gene expression of Flt3L. We conclude that expression of survivin is a downstream event of Flt3 signaling, which serves as an essential mechanism supporting survival of leukocytes during their differentiation, and maturation of dendritic cells, in RA.
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| 2. |
- Bjersing, Jan, 1966, et al.
(författare)
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Changes in pain and insulin-like growth factor 1 in fibromyalgia during exercise: the involvement of cerebrospinal inflammatory factors and neuropeptides
- 2012
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354. ; 14:4
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Introduction: Fibromyalgia (FM) is characterized by chronic pain. Impaired growth hormone responses and reduced serum insulin-like growth factor 1 (IGF-1) are common in FM. The aim was to examine changes in serum IGF-1, cerebrospinal fluid (CSF), neuropeptides, and cytokines during aerobic exercise in FM patients. Methods: In total, 49 patients (median age, 52 years) with FM were included in the study. They were randomized to either the moderate- to high-intensity Nordic Walking (NW) program (n = 26) or the supervised low-intensity walking (LIW) program (n = 23). Patients participated in blood tests before and after 15 weeks of aerobic exercise. Changes in serum levels of free IGF-1, pain rating on a 0- to 100-mm scale, pain threshold, and 6-minute walk test (6MWT) were examined. CSF, neuropeptides, matrix metalloproteinase 3 (MMP-3), and inflammatory cytokines were determined. Nonparametric tests were used for group comparisons and correlation analyses. Results: Serum free IGF-1 levels did not change during 15 weeks of exercise between the two groups, although the 6MWT significantly improved in the NW group (p = 0.033) when compared with LIW. Pain did not significantly change in any of the groups, but tended to decrease (p = 0.052) over time in the total group. A tendency toward a correlation was noted between baseline IGF-1 and a decrease of pain in response to exercise (r = 0.278; p = 0.059). When adjusted for age, this tendency disappeared. The change in serum free IGF-1 correlated positively with an alteration in CSF substance P (SP) levels (rs = 0.495; p = 0.072), neuropeptide Y (NPY) (rs = 0.802; p = 0.001), and pain threshold (rs = 0.276; p = 0.058). Differing CSF SP levels correlated positively to a change in pain threshold (rs = 0.600; p = 0.023), whereas the shift in CSF MMP-3 inversely correlated with an altered pain threshold (rs = -0.569; p = 0.034). Conclusions: The baseline level of serum free IGF-1 did not change during high or low intensity of aerobic exercise. Changes in IGF-1 correlated positively with a variation in CSF SP, NPY, and pain threshold. These data indicate a beneficial role of IGF-1 during exercise in FM. Trial registration: ClinicalTrials.govNCT00643006.
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| 3. |
- Bokarewa, Maria, 1963, et al.
(författare)
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Smoking is associated with reduced leptin and neuropeptide Y levels and higher pain experience in patients with fibromyalgia.
- 2014
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Ingår i: Mediators of inflammation. - : Hindawi Limited. - 1466-1861 .- 0962-9351. ; 2014
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Tidskriftsartikel (refereegranskat)abstract
- Smoking deregulates neuroendocrine responses to pain supporting production of neuropeptide Y (NpY) by direct stimulation of nicotinic receptors or by inhibiting adipokine leptin. Present study addressed the effect of cigarette smoking on adipokines and pain parameters, in 62 women with fibromyalgia (FM) pain syndrome with unknown etiology. Pain was characterized by a visual analogue scale, tender point (TP) counts, pressure pain threshold, and neuroendocrine markers NpY and substance P (sP). Levels of IGF-1, leptin, resistin, visfatin, and adiponectin were measured in blood and cerebrospinal fluid. Current smokers (n = 18) had lower levels of leptin compared to ex-smokers (n = 25, P = 0.002), while the expected NpY increase was absent in FM patients. In smokers, this was transcribed in higher VAS-pain (P = 0.04) and TP count (P = 0.03), lower pain threshold (P = 0.01), since NpY levels were directly related to the pain threshold (rho = 0.414) and inversely related to TP counts (rho = -0.375). This study shows that patients with FM have no increase of NpY levels in response to smoking despite the low levels of leptin. Deregulation of the balance between leptin and neuropeptide Y may be one of the essential mechanisms of chronic pain in FM.
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| 4. |
- Dehlin, Mats, 1968, et al.
(författare)
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Cerebrospinal Flt3 ligand correlates to tau protein levels in primary Sjögren's syndrome.
- 2013
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Ingår i: Scandinavian journal of rheumatology. - : Informa UK Limited. - 1502-7732 .- 0300-9742. ; 42:5, s. 394-399
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Primary Sjögren's syndrome (pSS) is an autoimmune disease affecting the exocrine glands and internal organs including the central nervous system (CNS). The fms-related tyrosine kinase 3 ligand (Flt3L) is a maturation factor essential for brain homeostasis. Blood levels of Flt3L are increased in inflammatory diseases including the inflamed salivary glands in pSS. The present study evaluated the role of Flt3L in the CNS of patients with pSS and in two non-autoimmune conditions, fibromyalgia (FM) and Alzheimer's disease (AD). Method: Levels of Flt3L were measured in cerebrospinal fluid (CSF) and serum of patients with pSS (n = 15), FM (n = 29), and AD (n = 39) and related to CNS symptoms and to markers of inflammation and degeneration. Results: Levels of CSF Flt3L in pSS and AD were significantly lower than in FM (p = 0.005 and p = 0.0003, respectively). Flt3L in pSS correlated to tau proteins [total tau (T-tau), r = 0.679; phosphorylated tau (P-tau), r = 0.646] and to a marker for microglia activation, monocyte chemoattractant protein 1 (MCP-1). Similar correlations were present in FM and AD patients. One-third of pSS patients had low levels of CSF Flt3L. This group had decreased levels of amyloid precursor protein metabolites (Aβ40 and Aβ42) in CSF, which was not seen in FM patients. Conclusions: This study shows a strong correlation between CSF Flt3L and tau proteins in pSS patients suggesting ongoing degradation/remodelling in the CNS. In pSS patients, low levels of Flt3L were linked to changes in amyloid turnover and may represent processes similar to those in AD.
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| 5. |
- Dehlin, Mats, 1968
(författare)
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Differentiation factor Fms-like tyrosine kinase 3 ligand is a modulator of cell responses in autoimmune diseases
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Fms-like tyrosine kinase 3 (Flt3) is a receptor on common stem cell progenitors and has a crucial role in hematopoesis, regulating cell proliferation and differentiation in man and mice. The growth factor Flt3 is activated by its soluble ligand, Flt3-L, leading to differentiation of multipotent stem cells and lymphoid progenitors. Flt3-L functions as a differentiation factor for dendritic cells (DC) in the periphery. These properties of the Flt3/Flt3-L system lead us to further investigate the role of the growth factor Flt3-L in rheumatic disease. In paper I, Flt3-L was found to be strongly expressed at the site of inflammation in human RA, the joint. Levels of Flt3-L were significantly higher in the synovial fluid compared to serum in RA patients and levels of Flt3-L in RA synovial fluid were significantly higher compared to synovial fluid from non-inflammatory joint diseases. Furthermore, intra-articular administration of a B-cell line overexpressing Flt3-L resulted in highly erosive arthritis while inoculation of the same B-cell line without hyperexpression of Flt3-L did not induce erosivity and caused arthritis in a minority of cases. Thus, Flt3-L is expressed at the site of inflammation in human RA and facilitates tissue destructive properites in the joint cavity. In paper II, mice with antigen-induced arthritis, mBSA-arthritis, were treated with the Flt3-inhibitor sunitinib. Treatment was started together with mBSA immunization or together with the induction of arthritis. Abrogation of Flt3 signalling reduced the intensity of synovitis and the frequency of bone destruction. Inhibition of Flt3 reduced also the number of differentiated (mature) dendritic cells concomitant with reduction of antibody production and bone metabolism. In addition to this, we investigated the ability of mouse bone marrow cells to migrate towards Flt3-L in a migration assay. Flt3-L was found to be a potent chemoattractant facilitating mobilization of Flt3+ cells from the bone marrow. Thus, the processes of antigen presentation, influx of leukocytes into synovial tissue and bone remodelling are mediated by Flt3 signalling in antigen-induced arthritis. In paper III, Flt3-L in CSF correlated to levels of Tau and pTau of patients with Sjögrens syndrome, fibromyalgia and Alzheimers disease, implying involvement of Flt3L in brain homeostasis. Furthermore, CSF Flt3-L in pSS correlated to a marker for microglia activation, MCP-1. Levels of Flt3-L in CSF were significantly decreased in pSS, and AD, compared to FM. Low levels of Flt3-L were associated to low levels of amyloid degradation peptides in pSS and AD patients. Thus, in CNS of patients with pSS Flt3-L is strongly correlated to neuroaxonal plasticity and microglia activation and reduced levels of CSF-Flt3-L in pSS are linked to changes in tau and amyloid turnover resembling processes ongoing in AD patients. Taken together, these results indicate that Flt3-L is involved in the inflammatory and tissue remodelling processes in joints and neuroaxonal structures of the brain. Flt3/Flt3-L signalling is an essential regulator of antigen-induced processes in autoimmune diseases.
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| 6. |
- Dehlin, Mats, 1968, et al.
(författare)
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Inhibition of fms-like tyrosine kinase 3 alleviates experimental arthritis by reducing formation of dendritic cells and antigen presentation.
- 2011
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Ingår i: Journal of leukocyte biology. - : Oxford University Press (OUP). - 1938-3673 .- 0741-5400. ; 90:4, s. 811-7
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Tidskriftsartikel (refereegranskat)abstract
- TKs are intracellular signaling molecules essential for cell homeostasis. Inhibition of TKs is used in treatment of malignancies and diabetes mellitus. The present study evaluated the role of Flt3 in antigen-induced arthritis. Mice were immunized with mBSA, and arthritis was induced by an i.a. injection of mBSA. Treatment with the Flt3 inhibitor sunitinib was started together with mBSA immunization or together with the induction of arthritis. The mBSA-injected joints were evaluated morphologically for signs of synovitis and bone/cartilage destruction. Markers of bone metabolism and antibody responses were measured by ELISA. Maturation of DCs in the bone marrow and spleen was evaluated by flow cytometry. Sunitinib treatment reduced the intensity of synovitis and the incidence of bone destruction. The reduction in bone destruction was seen when the treatment was started at the time of immunization or at the time of arthritis induction. The antiarthritic effect was achieved by inhibition of DCs, reduction of antibody production, and bone metabolism. Inhibition of Flt3 is a potent antiarthritic mechanism reducing antigen presentation, synovial inflammation, and bone resorption. Down-regulation of TKs may be a useful tool in the treatment of human RA.
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