Treatment of severe psoriasis and psoriatic arthritis with leflunomide.
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Anti-Inflammatory Agents, Non-Steroidal↗
Biomedical subjects
R Mössner
Publications and source records attributed to R Mössner.
Modulation of serotonin transporter function by interleukin-4.
Serotonin (5-HT) is an important mediator of interactions between the nervous and immune systems. 5-HT signaling is regulated by the 5-HT transporter (5-HTT), which determines the magnitude and duration of serotonergic responses. Due to this important role, regulation of the 5-HTT by cytokines has been the focus of recent interest. A number of proinflammatory cytokines, including interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma, have been shown to upregulate the 5-HTT. In the present study we investigated the influence of interleukin-4 (IL-4), which acts as an anti-inflammatory cytokine in the central nervous system, on the 5-HTT. As a model system we used immortalized B lymphocytes, which not only express the 5-HTT, but also allow testing the co-modulatory influence of a recently described polymorphism in the 5-HTT gene promoter (5-HTTLPR) that is associated with anxiety- and depression-related behavioral traits. The results show that IL-4 induces a dose-dependent reduction of 5-HT uptake. This effect is preferentially seen in cell lines homozygous for the long, high-activity allele of the 5-HTTLPR. In conclusion, a picture of differential modulation of the 5-HTT by proinflammatory and anti-inflammatory cytokines is emerging, which may represent a fine-tuned mechanism to communicate the state of an immune response to the central nervous system.
Alleles↗
Allelic variation of serotonin transporter expression is associated with depression in Parkinson's disease.
Idiopathic Parkinson's disease (PD) is a common neurodegenerative disorder with prominent motor symptoms. However, depression is common in PD, affecting about 40% of PD patients. Since there is extensive evidence of degeneration of serotonin (5HT) neurons and loss of the 5HT transporter (5HTT) in PD, we assessed whether a functional polymorphism in the promoter of the 5HTT gene (5HTT gene-linked polymorphic region, 5HTTLPR), which determines high or low 5HT uptake, is associated with depressive symptomatology in PD patients. We found that patients with the short allele of the 5HTTLPR had significantly higher scores on the Hamilton Depression Scale. A functional promoter polymorphism of the monoamine oxidase A (MAOA) gene showed no association. Thus, the 5HTTLPR but not the MAOA gene promoter-associated polymorphism may be a risk factor for depression in PD patients, while neither polymorphism increases the risk for development of Parkinson's disease itself.
Alleles↗
A missense mutation in a novel gene encoding a putative cation channel is associated with catatonic schizophrenia in a large pedigree.
Schizophrenia is a common and etiologically heterogeneous disorder. Although inheritance of schizophrenic syndromes is complex with genetic and environmental factors contributing to the clinical phenotype, periodic catatonia, a familial subtype of catatonic schizophrenia, appears to be transmitted in an autosomal dominant manner. We report here that a Leu309Met mutation in WKL1, a positional candidate gene on chromosome 22q13.33 encoding a putative non-selective cation channel expressed exclusively in brain, co-segregates with periodic catatonia in an extended pedigree. Structural analyses revealed that this missense mutation results in conformational changes of the mutant protein. Our results not only underscore the importance of genetic mechanisms in the etiology of schizophrenic syndromes, but also provide a better understanding of the pathogenesis and incapacitating course of catatonic schizophrenia and related disorders.
Amino Acid Sequence↗
Serotonin transporter function is modulated by brain-derived neurotrophic factor (BDNF) but not nerve growth factor (NGF).
The serotonin transporter (5-HTT) regulates serotonergic neurotransmission by determining the magnitude and duration of serotonergic responses. We have recently described a polymorphism in the 5-HTT gene promoter (5-HTTLPR) which influences the function of the 5-HTT and is associated with several psychiatric disorders. Immortalized B lymphocytes express the 5-HTT, and a B lymphocyte line has been shown to express the receptor for brain-derived neurotrophic factor, trkB. Since brain-derived neurotrophic factor (BDNF) is a specific growth and differentiation factor for serotonergic neurons, we assessed whether BDNF is able to modulate 5-HTT function in B lymphoblasts. Nerve growth factor (NGF), another neurotrophin which acts via the trkA receptor, was also studied. Eight immortalized B lymphoblast lines were generated and genotyped for the 5-HTTLPR. After treatment with BDNF or NGF, 5-HT uptake and proliferation of the cell lines were assessed. Two of the B cell lines showed a dose-dependent reduction of 5-HT uptake after exposure to BDNF. Both of these cell lines were homozygous for the long allele of the 5-HTTLPR. NGF did not influence 5-HT uptake or cellular proliferation in any of the cell lines. Thus, BDNF but not NGF may influence 5-HT uptake in some B lymphocytes. The fact that regulation of the 5-HTT was observed preferentially in cells of the long/long genotype indicates that presence of a short allele confers reduced regulatory capacity on the 5-HTT. In conclusion, B lymphoblasts represent a practical model for functional regulation of the 5-HTT by neurotrophins in serotonergic neurons.
Alleles↗
Differential regulation of adenosine A(1) and A(2A) receptors in serotonin transporter and monoamine oxidase A-deficient mice.
The serotonin (5HT) transporter (5HTT) removes 5HT from the synaptic cleft and is thus critical to the control of serotonergic neurotransmission. Mice with a targeted inactivation of the 5HTT represent a novel and unique tool to study serotonergic system functioning. Because the release of 5HT is regulated by adenosine, we investigated 5HTT-deficient mice for possible adaptive changes of adenosine A(1) and A(2A) receptors. A(1) and A(2A) receptors were studied by means of quantitative autoradiography using the radioligands [3H]8-cyclopentyl-1,3-dipropylxanthine and [3H]CGS 21680, respectively. A comparison of 5HTT knockout versus control mice revealed upregulation of A(1) receptors in the dorsal raphe nucleus (DRN, +21%), but not in any of the serotonergic projection areas, and downregulation of A(2A) receptors in basal ganglia. The adaptive changes of A(1) and A(2A) receptors in 5HTT-deficient mice are likely to represent a compensatory neuroprotective effect mediated by the adenosinergic modulatory system. For comparison, these receptors were also studied in monoamine oxidase A (MAOA) knockout mice and in 5HTT/MAOA double knockout mice. 5HTT/MAOA double knockout mice showed adaptive changes of adenosine A(1) and A(2A) receptors similar to 5HTT knockout mice, while investigation of MAOA-deficient mice revealed an upregulation of A(2A) receptors, which may relate to a role of both MAOA and adenosine A(2A) receptors in anxiety.
Animals↗
Effect of 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) on human serotonergic cells.
The tryptamine-derived dopaminergic neurotoxin 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline ('TaClo'), which was found to occur in humans after intake of the hypnotic chloral hydrate, was also shown to strongly disturb serotonergic cells. Incubation experiments using the human serotonergic cell line JAR clearly revealed TaClo to significantly reduce serotonin (5-HT) uptake (IC(50) = 59 microM) and to induce a distinct loss of cellular viability at increasing TaClo concentrations. In contrast to well-known serotonergic neurotoxins such as amphetamines, however, TaClo toxicity is not mediated by the 5-HT transporter (5-HTT). In the presence of the specific 5-HTT inhibitor imipramine, the uptake of TaClo into JAR cells was not reduced, hinting at an exclusively passive penetration of this highly lipophilic beta-carboline through cell membranes. Similar toxic effects towards JAR cells were also observed for the 5-HT-related TaClo analog 6-hydroxy-1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline ('6-OH-TaClo') (IC50 = 26 gM). The dopamine-derived alkaloid-type heterocycle 6,7-dihydroxy-1-trichloromethyl-1,2,3,4-tetrahydroisoquinoline ('DaClo'), by contrast, was found to be less toxic, showing only a weak inhibitory activity (IC50 = 260 microM) on 5-HT uptake. The pronounced toxicitiy of TaClo and 6-OH-TaClo against serotonergic cells became also evident from morphological findings: Dose-dependently, the survival of JAR cells was significantly impaired, while human dopaminergic IMR-32 cells were only moderately affected at similar toxin concentrations.
Biological Transport↗
Malignant pheochromocytoma with progressive paraparesis in von Hippel-Lindau disease.
Pheochromocytomas are a feature of the von Hippel-Lindau disease spectrum, a multisystem disorder of autosomal dominant inheritance. Pheochromocytomas are, however, observed during life with a lower frequency than other features of this disease, such as retinal angiomas, haemangioblastomas of the CNS, and renal carcinomas. We present the highly unusual case of a patient who required an emergency operation for an intradural extramedullary thoracic tumour which was clinically suggestive initially of neurinoma. We present evidence from NMR, histological and isotope scan investigations of this being a pheochromocytoma metastasis and of an additional right-sided paraganglioma at the same height. A detailed history revealed that this patient had suffered from four other pheochromocytomas and two other paragangliomas, in addition to retinal angiomatosis of von Hippel-Lindau disease. This case is extraordinary due to (i) the unusual site of the metastasis, (ii) the neurological requirement for an emergency operation of pheochromocytoma, (iii) metastasis of pheochromocytoma in von Hippel-Lindau disease (only eight previous cases), and (iv) the number of recurrent pheochromocytomas. It clearly demonstrates the necessity for frequent and life-long follow-up in von Hippel-Lindau disease.
Adrenal Gland Neoplasms↗
The serotonin transporter in Alzheimer's and Parkinson's disease.
The etiology of late-onset Alzheimer's disease (AD) and idiopathic Parkinson's disease (PD) is not known. In both disorders there is an extensive degeneration of serotonergic neurons, with corresponding losses of the serotonin (5HT) transporter (5HTT), which is responsible for the reuptake of 5HT from the synaptic cleft. An increasing body of evidence indicates that allelic variation of the 5HTT gene promoter (5HTT gene-linked polymorphic region, 5HTTLPR) determines high or low 5HT uptake in normal human brain. Association studies show that the low-activity allele of the 5HTTLPR is a risk factor for late-onset AD. In PD, the 5HTTLPR influences the risk of developing depression, a common symptom in PD patients. A compromised serotonergic system thus plays an important role in the pathophysiology of both AD and PD.
Alleles↗
Functional characterization of the human PAX3 gene regulatory region.
Spatiotemporal expression of the PAX3 gene is tightly regulated during development. We have isolated and sequenced the 5'-flanking regulatory region of human PAX3. Primer extension and ribonuclease protection mapping revealed that transcription is initiated from a single start site downstream of a TATA-like motif in human brain and peripheral tissues. Functional dissection of the gene's 5'-flanking region, which had been fused to a luciferase reporter gene and transiently expressed in rhabdomyosarcoma (RD) and cos-7 cells, indicated that the upstream region of PAX3 contains multiple positive and negative cis-acting regulatory elements. While the basal promoter is likely to be driven by two CCAAT boxes located at nucleotide positions -90 and -135, a cluster of regulatory elements acting as a strong repressor was detected between nucleotides -1200 and -650. Comparison of human and murine sequences revealed more than 90% identity in this segment. A polymorphic (CA)n repeat sequence and a G/C substitution are located 337 bp and 328 bp upstream of the transcription start site, respectively. PCR-based systematic screening for length variations in 225 unrelated individuals of a Caucasian population showed a bimodal distribution of multiple alleles containing between 13 and 30 repeat units. Although the (CA)25 variant of this PAX3 gene-linked polymorphic region (PAX3LPR) conferred lower transcriptional efficiency on the PAX3 promoter, a regulatory impact of the PAX3LPR on PAX3 expression related to brain plasticity and function remains to be demonstrated.
Alleles↗
Mosaicism for a serotonin transporter gene promoter-associated deletion: decreased recombination in depression.
Transcriptional activity of the human serotonin transporter gene (5HTT) is modulated by complex interaction of multiple genomic and cellular factors. Variability of a polymorphic repetitive element (5HTTLPR) is associated with anxiety, depression, and aggression-related traits and may influence the risk to develop affective spectrum disorders. 5HTTLPR variants display a unique DNA secondary structure that has the potential to regulate the transcriptional activity of the associated 5HTT promoter. The structure of the 5HTTLPR is also likely to precipitate a 381-bp somatic deletion in the 5HTT's promoter region [del(17)(q11.2)] that is observed in 20-60% of genomic DNA isolated from mononuclear blood cells and postmortem brain. The localization of the deletion breakpoints adjacent to identical putative signal sequences (CAGCC) suggests a V(D)J recombinase-like rearrangement event. In comparison with healthy controls, del(17)(q11.2)/wildtype sequence ratios showed a decrease of the deleted variant in recurrent unipolar depression. Our results also suggest that mosaicism of del(17)(q11.2) is likely to be regulated by tissue-specific as well as 5HTTLPR-dependent mechanisms. The findings confirm that the pericentric region of human chromosome 17 is highly unstable and furnishs additional evidence for intricate complexity of 5HTT regulation under physiological condition and in disease.
Adult↗
Regulation of PAX-6 gene transcription: alternate promoter usage in human brain.
We have isolated and characterized the 5'-flanking regulatory region of the human PAX-6 gene. Mapping of transcription initiation sites revealed the existence of an additional non-coding 5' exon, exon 1A. Functional analyses indicated that PAX-6 transcription is regulated by two distinct promoters, A and B, resulting in alternative transcription of exon 1A or 1B and joint transcription of exons 2 to 13. While a single initiation site was identified for exon 1A, transcription of exon 1B appears to be initiated from more than one site downstream of the promoter B-associated TATA motif. Multiple potential binding sites for transcription factors were found in the regions of promoter A and B. Although a 1.1-kb fragment of promoter A and a 1.5 kb fragment of promoter B, which had been fused to a reporter gene and transiently expressed in cell lines, displayed constitutive promoter activity, transcription of PAX-6 driven by promoter B was considerably higher than by promoter A in various regions of human postmortem brain. Transcript PAX-6B was primarily expressed in cerebellar cortex, whereas relatively low concentrations were detected in other brain areas. Functional dissection by serial deletions revealed several clusters of both activating elements and cell-selective silencers within the regulatory regions upstream of exon 1A and 1B. Coexpression of the promoter B constructs with a vector expressing PAX-6 modulated promoter B activity, thus indicating autoregulation by PAX-6 transcription. In conclusion, our findings suggest that PAX-6 transcription is regulated by alternate usage of promoter A and B, and that in adult human brain expression of PAX-6 is primarily controlled by promoter B. Alternate promoter usage and differential PAX-6 transcription are likely to play a critical role in brain development and neuroplasticity.
3T3 Cells↗
Genetically driven variation in serotonin uptake: is there a link to affective spectrum, neurodevelopmental, and neurodegenerative disorders?
Serotonin (5-HT) is an important regulator of morphogenetic activities during early central nervous system development, including cell proliferation, migration, and differentiation. The 5-HT transporter (5-HTT) plays a pivotal role in brain 5-HT homeostasis. It is also the initial target for both antidepressant drugs and drugs of abuse, some of which are potent neurotoxins. A polymorphism in the 5'-flanking regulatory region of the 5-HTT gene that results in allelic variation of 5-HTT expression is associated with anxiety-related personality traits and may influence the risk of developing affective disorders. Progress in 5-HTT gene inactivation studies are also changing views of the relevance of adaptive 5-HT uptake function in brain development and plasticity as well as processes underlying drug dependence and neurodegeneration. Despite evidence for a potential role of the 5-HTT in the integration of synaptic connections in the mammalian brain during development, adult life, and old age, detailed knowledge of the molecular mechanisms involved in these fine-tuning processes is just beginning to emerge. Integration of various strategies, including molecular genetic, transgenic, and gene transfer techniques, will allow elucidation of the 5-HTT's role in brain development, plasticity, and degeneration as well as in affective illness, drug abuse, and dementia.
Adult↗
A promoter-associated polymorphic repeat modulates PAX-6 expression in human brain.
The PAX-6 gene plays a critical role in neurodevelopment and brain plasticity. While transcription of human PAX-6 is regulated by alternate usage of two distinct promoters termed A and B, expression in adult human brain is primarily controlled by promoter B. We now report that a novel polymorphic dinucleotide repeat sequence with the structure (AC)m(AG)n is located approximately 1 kb upstream of the transcription initiation site associated with promoter B. PCR-based systematic screening for length variations in a caucasian population showed a skewed distribution of multiple alleles containing between 24 and 36 repeat units. In 217 unrelated individuals, the frequency of alleles in the range between 25 and 29 repeats was 90%, with the 26 repeat allele alone accounting for 50%; the heterozygosity rate was 65%. Variants of this PAX-6 gene-linked polymorphic region (PAX-6LPR) had different transcriptional efficiencies when fused to a luciferase reporter gene and transfected into Cos-7 cells. Promoter activity of variants with >/=29 repeats was 4- to 9-fold higher than that of the 26 repeat allele. The influence of the PAX-6LPR on PAX-6 expression was confirmed in postmortem cerebellum from individuals with different genotypes. mRNA levels were 2-fold higher in genotypes with long alleles compared to those with short alleles. Allelic variation in PAX-6 expression may be a determinant of interindividual differences in brain plasticity and function.
Alleles↗
Mood disorders and dysfunction of the hypothalamic-pituitary-adrenal axis in multiple sclerosis: association with cerebral inflammation.
OBJECTIVE: To investigate the association between affective and neuroendocrine abnormalities, commonly observed in multiple sclerosis, with inflammatory disease activity. DESIGN: Cross-sectional design. Twenty-three patients with definite relapsing-remitting multiple sclerosis and age- and sex-matched control subjects were investigated. Depression and anxiety were assessed using structured interviews, self-report measures, and Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised criteria. Neurologic impairment was assessed by the Kurtzke Expanded Disability Status Scale and function of hypothalamic-adrenal-pituitary axis was analyzed using a corticotropin-releasing hormone stimulation test after dexamethasone suppression. Inflammatory disease activity was evaluated first by routine and experimental laboratory tests, and second by magnetic resonance assessment of gadolinium uptake of multiple sclerotic plaques. SETTING: University hospital, a major provider of acute neurologic care. RESULTS: Compared with controls, patients with multiple sclerosis had higher scores on depression and anxiety scales and exhibited a failure of suppression of cortisol release after dexamethasone pretreatment. Both affective symptoms and neuroendocrine abnormalities were correlated with cerebrospinal fluid white blood cell counts and presence of gadolinium-enhancing lesions on magnetic resonance images; however, no association with the degree of neurologic impairment was observed. CONCLUSION: Affective and neuroendocrine disorders were related to inflammatory disease activity but not to degree of disability, supporting the hypothesis that these symptoms are causally associated with brain injury.
Adult↗
Role of serotonin in the immune system and in neuroimmune interactions.
Serotonin (5-HT) is one of the most extensively studied neurotransmitters of the central nervous system. 5-HT is, however, also present in a variety of peripheral tissues including in constituents of the immune system. The function of 5-HT in the immune system has received increasing attention since about 1984, but has been reviewed only once, in 1985. In recent years, modern techniques of molecular biology such as reverse-transcriptase polymerase chain reaction and targeted gene disruption have made it possible to study new important aspects of 5-HT in the immune system. In the first part of the review, we explore whether 5-HT is involved in interactions between the central nervous and immune systems. It emerges that 5-HT may mediate interactions of these two systems by four different pathways. In the second part, we dissect the functional roles of 5-HT in the immune system. We describe the distribution of 5-HT receptors and the 5-HT transporter on immune cells and estimate which levels 5-HT may attain in the extracellular space in physiological conditions and under pathological circumstances such as inflammation, thrombosis, and ischemia. At these 5-HT concentrations, four major functions for 5-HT emerge. These include T cell and natural killer cell activation, delayed-type hypersensitivity responses, production of chemotactic factors, and natural immunity delivered by macrophages. Finally, we discuss promising future avenues to further advance knowledge of the role of 5-HT in the immune system and in neuroimmune interactions.
Animals↗
Insertion/deletion variant (-141C Ins/Del) in the 5' regulatory region of the dopamine D2 receptor gene: lack of association with schizophrenia and bipolar affective disorder. Short communication.
A possible dysregulation of dopaminergic neurotransmission has been implicated in the aetiology of schizophrenic psychoses, in particular of paranoid-hallucinatory states, and of the manic episodes of bipolar affective disorder. In the present study we analysed allelic and genotypic variations of a recently described functional deletion/insertion variant (-141C Ins/Del) in the 5' flanking region of the human dopamine D2 receptor gene. We investigated a total of 620 unrelated individuals, comprising 260 schizophrenic patients, 70 patients with bipolar affective disorder, and 290 population controls. Analysis of the -141C Ins/Del variant revealed that the schizophrenic, bipolar affective and control groups did not differ significantly regarding genotype frequencies and allele frequencies. No evidence of an allelic association with either a family history of schizophrenic psychosis or a diagnosis of schizophrenia of the paranoid type (according to ICD 10) was found. Our findings indicate that the -141C Del variant in the 5' flanking region of the human dopamine D2 receptor gene is unlikely to play a substantial role in genetic predisposition to major psychiatric disorders in Caucasians.
Adult↗
Enhancement of serotonin transporter function by tumor necrosis factor alpha but not by interleukin-6.
Serotonin (5-HT) is a prime candidate for studies of the interaction between the nervous and immune systems, since it is both an important neurotransmitter and released at high concentrations at sites of inflammation. Serotonergic neurotransmission is regulated by the 5-HT transporter (5-HTT), which determines the magnitude and duration of serotonergic responses. Since tumor necrosis factor alpha (TNF-alpha) and interleukin-6 are two inflammatory mediators that are central to the initiation of inflammation, we studied the impact of these cytokines on the 5-HTT. As model system we used a cell line which constitutively expresses the 5-HTT, namely the choriocarcinoma cell line JAR. We found that TNF-alpha enhances 5-HT uptake, with a doubling of the maximal velocity of uptake. Interleukin-6, on the other hand, had no effect. We thus show for the first time that the cytokine TNF-alpha modulates 5-HTT function. Furthermore, we propose a molecular mechanism for this effect. Since both 5-HT and TNF-alpha are elevated at sites of inflammation, TNF-alpha may act to renormalize 5-HT levels by way of its effect on the 5-HTT. This is especially important for the central nervous system, where the TNF-alpha effect shown here can aid in preventing disturbances of serotonergic neurotransmission.
Carrier Proteins↗