DNA damage checkpoint control of mitosis in fission yeast.
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14-3-3 Proteins↗
Biomedical subjects
B Moser
Publications and source records attributed to B Moser.
Systemic neutralization of interleukin-8 markedly reduces neutrophilic pleocytosis during experimental lipopolysaccharide-induced meningitis in rabbits.
Interleukin-8 (IL-8) is elevated in the cerebrospinal fluid (CSF) of patients with meningitis and is proposed to participate in subarachnoid-space pleocytosis. However, intracisternal injection of IL-8 into rabbits failed to induce indices typical of meningitis (leukocyte, tumor necrosis factor, or protein accumulation in the CSF or histopathological changes), indicating that merely increasing the CSF level of this chemokine is insufficient to induce inflammation in this anatomical site. IL-8 treatment did not affect inflammatory responses to subsequently intracisternally administered lipopolysaccharide (LPS). IL-8 was chemotactic for rabbit neutrophils in vitro, and subcutaneous injection of IL-8 (diluted in buffer or CSF) proved the in vivo activity of this peptide and suggested the absence of an IL-8 inhibitor in normal rabbit CSF. LPS-dependent pleocytosis was only slightly diminished by intracisternally administered murine anti-rabbit IL-8 monoclonal antibody (MAb) WS-4 but was dramatically reduced by intravenously administered MAb. Therefore, elevated CSF IL-8 levels may contribute to, but cannot solely account for, neutrophil influx into the subarachnoid space during meningitis. However, inhibition of IL-8 activity of the bloodstream side of the blood-brain barrier effectively reduces pleocytosis, indicating a central role of IL-8 in neutrophil influx into CSF during bacterial meningitis. Thus, inhibition of IL-8 is a possible therapeutic target for adjunct treatment of meningitis.
Animals↗
[Physical exercise impairs the acute stage of adaptation to moderate altitude].
UNLABELLED: A recent study has reported the impairment of high altitude adaptation capacity by physical exercise in a decompression chamber. The aim of our protocol was to evaluate if physical exercise at moderate altitude in the Alps would show a similar effect. 8 alpinists were examined in a randomised cross-over trial at 171 m and at 3000 m altitude under sedentary and under exercise condition (50% maximal workload on the bicycle ergometer four times 30 minutes during the first 6 hours of an 8 hour observation period at each altitude). At the beginning and at the end of each observation period AMS scores and arterial oxygen saturation SaO2 were measured. The differences of the AMS scores and the differences of SaO2 at both test conditions were compared at both altitudes. RESULTS: In comparison to sedentary condition, the differences between initial and final AMS scores at 3000 m altitude were significantly higher (-0.38 +/- 0.52 vs. -1.25 +/- 0.46, diff 0.88, 95% CI 0.58 to 1.17, p < 0.01), as well as the difference between initial and final SaO2 (-0.25 +/- 0.71% vs. 2.25 +/- 1.04%, diff. -2.5%, 95% CI for the diff. -3.59 to -1.41, p < 0.01). AMS score and SaO2 did not change after exercise at 171 m altitude. CONCLUSION: Physical exercise impairs the acute stage of adaptation to moderate altitude. This is mainly due to the exercise-induced exaggeration of arterial hypoxaemia.
Acute Disease↗
Structure and function of the murine chemokine receptor CXCR3.
The gene encoding the murine homologue of human CXCR3 exists in a single copy consisting of two exons with an intron interrupting the coding sequence between nucleotides 10 and 11. The deduced amino acid sequence is 86% identical to the predicted human sequence. Murine CXCR3 mRNA is detectable in bone marrow cells cultured in the presence of IL-2 but not unstimulated cells. It is also detectable at low abundance in normal mouse spleen, lymph node, mammary gland, and thymus. Transfection of murine CXCR3 in murine pre-B lymphocyte line (CXCR3++/L1.2) conferred binding of the ligands IP10, ITAC and Mig with K(D)'s of 1.35 +/- 0.56, 1.41 +/- 0.20, and 11.65 +/- 0.90 nM, respectively. Lower affinity binding was observed for several beta or CC chemokines (eotaxin, MCP-3, MIP3alpha and SLC/6Ckine/Exodus 2). ITAC, IP10 and Mig induced chemotaxis with an order of potency ITAC > IP10 = Mig. The chemokines also increased intracellular calcium concentration and were variably desensitized to repeated agonist stimulation. The hierarchy for cross- desensitization was ITAC > Mig > IP10. Thus, while Mig, ITAC and IP10 all act on the same receptor for binding and agonist stimulation, they may interact with different receptor conformational isoforms to produce divergent responses.
Amino Acid Sequence↗
Cytokines and chemokines in meningeal inflammation: biology and clinical implications.
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Central Nervous System Infections↗
Cardiorespiratory consequences of the hobble restraint.
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Acidosis↗
Interferon-inducible T cell alpha chemoattractant (I-TAC): a novel non-ELR CXC chemokine with potent activity on activated T cells through selective high affinity binding to CXCR3.
Chemokines are essential mediators of normal leukocyte trafficking as well as of leukocyte recruitment during inflammation. We describe here a novel non-ELR CXC chemokine identified through sequence analysis of cDNAs derived from cytokine-activated primary human astrocytes. This novel chemokine, referred to as I-TAC (interferon-inducible T cell alpha chemoattractant), is regulated by interferon (IFN) and has potent chemoattractant activity for interleukin (IL)-2-activated T cells, but not for freshly isolated unstimulated T cells, neutrophils, or monocytes. I-TAC interacts selectively with CXCR3, which is the receptor for two other IFN-inducible chemokines, the IFN-gamma-inducible 10-kD protein (IP-10) and IFN-gamma- induced human monokine (HuMig), but with a significantly higher affinity. In addition, higher potency and efficacy of I-TAC over IP-10 and HuMig is demonstrated by transient mobilization of intracellular calcium as well as chemotactic migration in both activated T cells and transfected cell lines expressing CXCR3. Stimulation of astrocytes with IFN-gamma and IL-1 together results in an approximately 400,000-fold increase in I-TAC mRNA expression, whereas stimulating monocytes with either of the cytokines alone or in combination results in only a 100-fold increase in the level of I-TAC transcript. Moderate expression is also observed in pancreas, lung, thymus, and spleen. The high level of expression in IFN- and IL-1-stimulated astrocytes suggests that I-TAC could be a major chemoattractant for effector T cells involved in the pathophysiology of neuroinflammatory disorders, although I-TAC may also play a role in the migration of activated T cells during IFN-dominated immune responses.
Amino Acid Sequence↗
B cell-attracting chemokine 1, a human CXC chemokine expressed in lymphoid tissues, selectively attracts B lymphocytes via BLR1/CXCR5.
Although most leukocytes, T lymphocytes in particular, respond to several different chemokines, there is virtually no information on chemokine activities and chemokine receptors in B lymphocytes. A putative chemokine receptor, BLR1, that is expressed in Burkitt's lymphoma cells and B lymphocytes was cloned a few years ago. Deletion of the gene for BLR1 yielded mice with abnormal primary follicles and germinal centers of the spleen and Peyer's patches, reflecting the inability of B lymphocytes to migrate into B cell areas. By screening expressed sequence tag DNA sequences, we have identified a CXC chemokine, termed B cell-attracting chemokine 1 (BCA-1), that is chemotactic for human B lymphocytes. BCA-1 cDNA encodes a protein of 109 amino acids with a leader sequence of 22 residues. The mature protein shares 23-34% identical amino acids with known CXC chemokines and is constitutively expressed in secondary lymphoid organs. BCA-1 was chemically synthesized and tested for activity on murine pre-B cells 300-19 transfected with BLR1 and on human blood B lymphocytes. In transfected cells, BCA-1 induced chemotaxis and Ca2+ mobilization demonstrating that it acts via BLR1. Under the same conditions, no activity was obtained with 10 CXC and 19 CC chemokines, lymphotactin, neurotactin/fractalkine and several other peptide ligands. BCA-1 was also a highly effective attractant for human blood B lymphocytes (which express BLR1), but was inactive on freshly isolated or IL-2-stimulated T lymphocytes, monocytes, and neutrophils. In agreement with the nomenclature rules for chemokine receptors, we propose the term CXCR5 for BLR1. Together with the observed disturbance of B cell colonization in BLR1/ CXCR5-deficient mice, the present results indicate that chemotactic recruitment by locally produced BCA-1 is important for the development of B cell areas of secondary lymphoid tissues.
Amino Acid Sequence↗
The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions.
T cells infiltrating inflammatory sites are usually of the activated/memory type. The precise mechanism for the positioning of these cells within tissues is unclear. Adhesion molecules certainly play a role; however, the intricate control of cell migration appears to be mediated by numerous chemokines and their receptors. Particularly important chemokines for activated/memory T cells are the CXCR3 ligands IP-10 and Mig and the CCR5 ligands RANTES, macrophage inflammatory protein-1alpha, and macrophage inflammatory protein-1beta. We raised anti-CXCR3 mAbs and were able to detect high levels of CXCR3 expression on activated T cells. Surprisingly, a proportion of circulating blood T cells, B cells, and natural killer cells also expressed CXCR3. CCR5 showed a similar expression pattern as CXCR3, but was expressed on fewer circulating T cells. Blood T cells expressing CXCR3 (and CCR5) were mostly CD45RO+, and generally expressed high levels of beta1 integrins. This phenotype resembled that of T cells infiltrating inflammatory lesions. Immunostaining of T cells in rheumatoid arthritis synovial fluid confirmed that virtually all such T cells expressed CXCR3 and approximately 80% expressed CCR5, representing high enrichment over levels of CXCR3+ and CCR5+ T cells in blood, 35 and 15%, respectively. Analysis by immunohistochemistry of various inflamed tissues gave comparable findings in that virtually all T cells within the lesions expressed CXCR3, particularly in perivascular regions, whereas far fewer T cells within normal lymph nodes expressed CXCR3 or CCR5. These results demonstrate that the chemokine receptor CXCR3 and CCR5 are markers for T cells associated with certain inflammatory reactions, particularly TH-1 type reactions. Moreover, CXCR3 and CCR5 appear to identify subsets of T cells in blood with a predilection for homing to these sites.
Animals↗
CCR5 is characteristic of Th1 lymphocytes.
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Arthritis, Rheumatoid↗
The chemokine receptor CXCR3 mediates rapid and shear-resistant adhesion-induction of effector T lymphocytes by the chemokines IP10 and Mig.
Integrin-mediated adhesion to the vascular endothelium is an essential step in leukocyte diapedesis. We show that the chemokines 10-kDa inflammatory protein (IP10) and monokine induced by IFN (Mig) induce rapid and transient adhesion of human IL-2-stimulated T lymphocytes (IL-2 T cells) to immobilized integrin ligands through their receptor CXCR3, which is selectively expressed on activated T cells. Induction of adhesion by IP10 and Mig was already observed at subnanomolar concentrations and was maximal at 5-10 nM, resulting in three- to sixfold increase in adhesion of IL-2 T cells over background. No effect was seen with resting naive/memory T cells which lack CXCR3 and migration responses to IP10 and Mig. Both chemokines are produced in human umbilical vein endothelial cells (HUVEC) upon stimulation with IFN-gamma and TNF-alpha. These chemokines induce IL-2 T cell adhesion also when captured on the surface of endothelial cells. Under conditions of flow, IL-2 T cells roll and rapidly adhere to IP10/Mig-expressing HUVEC, and anti-CXCR3 mAb treatment reduces arrest and firm adhesion. This is the first study that shows chemokine-induced adhesion in activated memory/effector T cells which represent the fraction of T cells that are selectively mobilized in inflammation. The critical role of IFN-gamma as inducer of IP10/Mig production in HUVEC indicates that these chemokines are essential mediators of effector T cell recruitment to IFN-gamma-dependent pathologies.
Cell Adhesion↗
The chemokine SLC is expressed in T cell areas of lymph nodes and mucosal lymphoid tissues and attracts activated T cells via CCR7.
Secondary lymphoid-tissue chemokine, SLC, also known as exodus-2 and 6Ckine, is a novel CC chemokine with selectivity for T lymphocytes and preferential expression in lymphoid tissues. We have studied its production, receptor usage and biological activities. High levels of SLC mRNA were detected in lymph nodes, the gastrointestinal tract and several gland tissues, but no expression was found by Northern blot analysis in freshly isolated or stimulated blood monocytes and lymphocytes, or neutrophils and eosinophils. In situ hybridization revealed constitutive expression of SLC in the T cell areas and the marginal zone of follicles in lymph nodes and the mucosa-associated lymphoid tissue, but not in B cell areas or sinuses. Comparison with immunocytochemical staining showed similarity between the in situ expression of SLC and the distribution of interdigitating dendritic cells but not with sinus-lining dendritic cells, macrophages or T lymphocytes. SLC induced chemotaxis of T lymphocytes and its activity increased considerably when the cells were conditioned with IL-2 or phytohemagglutinin (PHA). Under optimal conditions SLC had unusually high efficacy and induced the migration of up to 50 % of input T lymphocytes. SLC also induced Ca2+ mobilization in these cells. Similar responses were obtained with EBI1 ligand chemokine (ELC), and sequential stimulation with both chemokines led to cross-desensitization, suggesting that SLC acts via the ELC receptor, CCR7. This was confirmed using murine pre-B cells stably transfected with CCR7 which bound SLC with high affinity and showed chemotaxis and Ca2+ mobilization in response to both SLC and ELC. In T lymphocytes PHA and IL-2, which enhanced chemotactic responsiveness, also markedly enhanced CCR7 expression. In contrast to all known chemokine receptors, up-regulation of CCR7 by IL-2 was transient. A maximum was reached in 2-3 days and expression returned to initial levels within 8-10 days. The present study shows that SLC is constitutively produced within the T cell areas of secondary lymphoid organs and attracts T lymphocytes via CCR7.
Animals↗
Lymphocyte-specific chemokine receptor CXCR3: regulation, chemokine binding and gene localization.
Expression of CXCR3, the receptor for the CXC chemokines IFN-gamma-inducible 10-kDa protein (IP10) and monokine induced by IFN-gamma (Mig), in human T lymphocytes and their responses to IP10 and Mig were analyzed. About 40 % of resting T lymphocytes (and low numbers of B cells and natural killer cells) stained positive for CXCR3 but these cells did not express CXCR3 transcripts and did not respond to these chemokines. However, treatment with IL-2 with or without addition of phytohemagglutinin for 10 or more days resulted in cultures of fully responsive, CXCR3-positive T lymphocytes. Treatment with anti-CD3 antibodies in the presence or absence of soluble anti-CD28 antibodies was inhibitory. Addition of chondroitin sulfate C to CXCR3-expressing murine pre-B cells allowed the determination of high-affinity binding for Mig and IP10 with Kd of 0.9-1.2 nM and 0.2-0.3 nM, respectively, and 1.3 x 10(4) binding sites per cell. The gene for CXCR3 was localized on human chromosome Xq13 which is in clear contrast to all other chemokine receptor genes, suggesting unique function(s) for this receptor and its ligands that may lie beyond their established role in T cell-dependent immunity.
Chemokine CXCL10↗
Behavioral effects of 5-HT2C receptor antagonism in the substantia nigra zona reticulata of the 6-hydroxydopamine-lesioned rat model of Parkinson's disease.
Overactivity of the substantia nigra zona reticulata and the medial segment of the globus pallidus are responsible for the generation of symptoms in Parkinson's disease. Reducing the activity of these regions has been shown to be a viable alternative to dopamine replacement in the symptomatic treatment of Parkinson's disease. 5-HT2C receptors in the substantia nigra zona reticulata are excitatory. In this study we have shown that intracerebral infusion of the selective 5-HT2C receptor antagonist SB 206553 (50 nmol) into the substantia nigra zona reticulata has an antiparkinsonian action in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease. SB 206553 did not affect locomotion when injected into the nonparkinsonian substantia nigra. Furthermore, we have demonstrated that systemic administration of selective 5-HT2C receptor antagonists SB 200646A (20 mg/kg) and SB 206553 (20 mg/kg) can potentiate the antiparkinsonian action of the dopamine D2 receptor agonist quinpirole in the 6-hydroxydopamine-lesioned rat. Hence, 5-HT2C receptor antagonists may be useful adjuncts to dopamine agonists in the treatment of Parkinson's disease.
Animals↗
Lymphocyte responses to chemokines.
Today, almost three dozen human chemokines have been identified. The main function of these soluble proteins is the recruitment of leukocytes to sites of infection and inflammation. This review emphasizes the new developments in the field of lymphocyte responses to chemokines. Notably, it was shown that lymphocytes require stimulation to become responsive to chemokines, a process that is closely linked to chemokine receptor expression. As an exception, one chemokine, SDF-1, is a highly effective chemoattractant for non-activated T lymphocytes and progenitor B cells. Of particular interest are the chemokines IP10 and Mig which bind to a receptor with selective expression in activated T lymphocytes and, therefore, may be critical mediators of T lymphocyte migration in T cell-dependent immune-responses. All other chemokines with activities in lymphocytes do also induce responses in monocytes and granulocytes. The involvement of chemokine receptors in HIV infection is briefly mentioned, while other interesting areas in chemokine research, such as hematopoiesis and angiogenesis, are not discussed.
Cell Adhesion↗
Human chemokines: role in lymphocyte trafficking.
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Animals↗
Functional expression of the eotaxin receptor CCR3 in T lymphocytes co-localizing with eosinophils.
BACKGROUND: The chemokine eotaxin is produced at sites of allergic inflammation, binds selectively to the chemokine receptor CCR3 and attracts eosinophil and basophil leukocytes, which express high numbers of this receptor. Responses of T lymphocytes to eotaxin have not been reported so far. We have investigated the expression of CCR3 in T lymphocytes and analysed the properties and in vivo distribution of T lymphocytes expressing this receptor. RESULTS: In search of chemokine receptors with selective expression in T lymphocytes, we have isolated multiple complementary DNAs (cDNAs) encoding CCR3 from a human CD4+ T-cell cDNA library. T-lymphocyte clones with selectivities for protein and non-protein antigens were analysed for expression of CCR3 and production of Th1- and Th2-type cytokines. Of 13 clones with surface CCR3, nine secreted enhanced levels of interleukin-4 and/or interleukin-5, indicating that CCR3 predominates in Th2-type lymphocytes. CCR3+ T lymphocytes readily migrated in response to eotaxin, and showed the characteristic changes in cytosolic free calcium. Immunostaining of contact dermatitis, nasal polyp and ulcerative colitis tissue showed that CCR3+ T lymphocytes are recruited together with eosinophils and, as assessed by flow cytometry, a large proportion of CD3+ cells extracted from the inflamed skin tissue were CCR3+. By contrast, CCR3+ T lymphocytes were absent from tissues that lack eosinophils, as demonstrated for normal skin and rheumatoid arthritis synovium. CONCLUSIONS: We show that T lymphocytes co-localizing with eosinophils at sites of allergic inflammation express CCR3, suggesting that eotaxin/CCR3 represents a novel mechanism of T-lymphocyte recruitment. These cells are essential in allergic inflammation, as mice lacking mature T lymphocytes were insensitive to allergen challenge. Surface CCR3 may mark a subset of T lymphocytes that induce eosinophil mobilization and activation through local production of Th2-type cytokines.
Cell Movement↗