The role of migrating leukocytes in IL-1β-induced up-regulation of kinin B(1) receptors in rats

1. The present study examines the role of migrating leukocytes in the ability of IL-1β to induce the functional up-regulation of B(1) receptors, as assessed by kinin B(1) agonist-induced oedema in the rat paw. 2. Pre-treatment with the PAF receptor antagonist WEB 2086 inhibited des-Arg(9)-BK-induced oedema in IL-1β-treated paws, while the LTB(4) receptor antagonist CP105696 had no effect. Des-Arg(9)-BK-induced paw oedema was also inhibited by pre-treatment with the selectin blocker fucoidin or by an anti-CD-18 monoclonal antibody. 3. I.d. injection of IL-1β produced a 5 – 10-fold increase of myeloperoxidase (MPO) activity in the rat paw. The increase in MPO activity was significantly inhibited by WEB 2086 (46±9%), fucoidin (68±5%) or the CD-18 antibody (84±3%). In contrast, i.d. injection of TNFα a dose known to upregulate the B(1) receptor functionally did not induce any significant increase in MPO activity. 4. Des-Arg(9)-BK alone had no effect in MPO activity but enhanced (by about 40%) the response induced by IL-1β, an effect prevented by the B(1) receptor antagonist des-Arg(9)-[Leu(8)]-BK. 5. The concentration of TNF-α was increased in the paws after i.d. injection of IL-1β. Pre-treatment with fucoidin, WEB 2086, anti-CD-18 or CP 105695, significantly reversed the local increases in TNF-α concentrations (80±2; 75±4, 73±3 and 40±2%), respectively. 6. Finally, IL-1β induced an increase of B(1) receptor mRNA levels in the rat paw, an effect which was prevented by fucoidin treatment. 7. Taken together, these results indicate that up-regulation of B(1) receptors in the rat paw following IL-1β seems to involve the local recruitment of neutrophils and subsequent local TNF-α production. The cross-talk between kinins, cytokines and leukocytes implicate B(1) receptors in chronic inflammatory diseases

Presence of Reactive Microglia and Neuroinflammatory Mediators in a Case of Frontotemporal Dementia with P301S Mutation

Background: Recent findings, showing the presence of an inflammatory process in the brain of transgenic mice expressing P301S mutated human tau protein, indicate that neuroinflammation may contribute to tau-related degeneration in frontotemporal dementia and parkinsonism linked to chromosome 17 with tau mutations (FTDP-17T). Objective: To investigate the occurrence of neuroinflammatory changes in the brain of a patient affected by FTDP-17T associated with the P301S mutation and showing a frontotemporal dementia phenotype as well as in the brain of a patient affected by another FTDP-17T phenotype: multiple system tauopathy with presenile dementia. Methods: We used immunohistochemical methods to visualize activated microglia, interleukin-1 beta (IL-1 beta)-, cyclooxygenase-2 (COX-2)-expressing cells. Results: In the brain of the patient with the P301S mutation, a strong neuroinflammatory reaction was present. Activated microglia/infiltrating macrophages expressing the cluster of differentiation 68 and major histo-campatibility complex class II cell surface receptors, encoded by the human leukocyte antigen DP-DQ-DR, were detected in the cortex and hippocampus. IL-1 beta and COX-2 expression were induced in neuronal and glial cells. These neuroinflammatory changes were different from those observed in the brain of the patient bearing the +3 mutation, where macrophage infiltration was absent, microglial cells displayed an earlier stage of activation and COX-2 was not detected. Conclusions: Our findings suggest that microglial activation and the production of proinflammatory mediators by phospho-tau-positive neurons and glial cells may differentially contribute to neuronal death and disease progression in neurodegenerative tauopathies