ABSTRACT
Over the past decade there has been significant pressure to minimise emissions and safety risks related to commercial driving. This pressure to meet the triple bottom line of cost, environment, and society has often resulted in the rapid application of vehicle technologies designed to mitigate undesired effects. Often the cognitive and behavioural effects of technologies on the commercial driver have not received in-depth analysis to determine comprehensive viability. As such, this paper aims to identify a timescale for implementation for future technologies for UK road freight, and likely associated human factors issues, improving upon the currently employed 'trial-and-error' approach to implementation which may carry high economic, environmental, safety-related risk. Thought experiments are carried out to broadly explore these future systems. Furthermore, this work aims to examine whether technology alone will be enough to meet future CO2 reduction targets, and assess the role of behavioural and systems interventions for future research.
Subject(s)
Automobile Driving/psychology , Motor Vehicles , Safety , Technology Transfer , Vehicle Emissions/prevention & control , Attention , Behavior , Carbon Dioxide , Cross-Sectional Studies , Equipment Design , Ergonomics , Feedback , Humans , Internal-External Control , Interviews as Topic , Time FactorsABSTRACT
Extracellular signals are transduced intracellularly by multiple pathways, resulting in alterations in the transcription and translation of specific proteins. The end result of some of these signalling pathways is the production of proteins, including cytokines and matrix metalloproteinases, that are implicated in the pathogenesis of rheumatoid arthritis. This chapter includes a discussion of these signal transduction pathways, including tumour necrosis factor receptor signalling, interleukin-1, -4, and -6 receptor signalling, stress- and mitogen-activated protein kinase pathways, CD14 and Toll-like receptor signalling, and T cell signal transduction. The known effects of currently available rheumatoid arthritis (RA) therapeutics on these signalling pathways are also reviewed. In addition, potential future targets for therapeutic intervention in RA are discussed.
Subject(s)
Arthritis, Rheumatoid/metabolism , Drosophila Proteins , Receptors, Cell Surface/metabolism , Signal Transduction/physiology , Arthritis, Rheumatoid/etiology , Arthritis, Rheumatoid/therapy , Lipopolysaccharide Receptors/metabolism , MAP Kinase Signaling System , Membrane Glycoproteins/metabolism , Mitogen-Activated Protein Kinases/metabolism , Receptors, Antigen, T-Cell/metabolism , Receptors, Cytokine/metabolism , Toll-Like ReceptorsABSTRACT
OBJECTIVE: To determine whether TIA-1 differentially regulates the production of tumor necrosis factor a (TNFalphalpha) in macrophages and lymphocytes. METHODS: Peritoneal macrophages derived from wild-type and TIA-1-/- mice were cultured in the absence or presence of lipopolysaccharide (LPS) before comparison of the production of TNFalpha protein by intracellular flow cytometry and the secretion of TNFalpha protein by enzyme-linked immunosorbent assay. In parallel experiments, splenocytes were cultured in the absence or presence of concanavalin A (Con A), phorbol myristate acetate (PMA)/ionomycin, or anti-CD3/anti-CD28 before comparing the production of TNFalpha protein. Finally, the relative expression of TIA-1 protein in macrophages and splenocytes was compared using immunoblotting analysis. RESULTS: LPS-activated peritoneal macrophages derived from TIA-1-/- mice produced significantly more TNFalpha than macrophages from wild-type controls. In contrast, splenic lymphocytes (CD3+, CD4+, or CD8+) derived from wild-type and TIA-1-/- mice produced similar amounts of TNFalpha in response to Con A, PMA/ionomycin, or anti-CD3/anti-CD28. Lymphocytes and macrophages expressed similar amounts of TIA-1 protein, indicating that differential expression of TIA-1 cannot account for these results. CONCLUSION: TIA-1 is the target of a regulatory pathway that operates in activated macrophages, but not in activated lymphocytes. Developing drugs that target this pathway might prevent the pathologic overexpression of TNFalpha without subverting the T lymphocyte response to microbial pathogens.
Subject(s)
Macrophages/immunology , Membrane Proteins/genetics , Membrane Proteins/immunology , Proteins , RNA-Binding Proteins/genetics , RNA-Binding Proteins/immunology , T-Lymphocytes/immunology , Tumor Necrosis Factor-alpha/biosynthesis , Animals , Antibodies/pharmacology , CD28 Antigens/immunology , CD3 Complex/immunology , Carcinogens/pharmacology , Concanavalin A/pharmacology , Female , Flow Cytometry , Ionomycin/pharmacology , Ionophores/pharmacology , Lipopolysaccharides/pharmacology , Macrophages/drug effects , Macrophages/metabolism , Male , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , RNA-Binding Proteins/metabolism , T-Cell Intracellular Antigen-1 , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism , Tetradecanoylphorbol Acetate/pharmacologyABSTRACT
TIA-1 and TIAR are related proteins that bind to an AU-rich element (ARE) in the 3' untranslated region of tumor necrosis factor alpha (TNF-alpha) transcripts. To determine the functional significance of this interaction, we used homologous recombination to produce mutant mice lacking TIA-1. Although lipopolysaccharide (LPS)-stimulated macrophages derived from wild-type and TIA-1(-/-) mice express similar amounts of TNF-alpha transcripts, macrophages lacking TIA-1 produce significantly more TNF-alpha protein than wild-type controls. The half-life of TNF-alpha transcripts is similar in wild-type and TIA-1(-/-) macrophages, indicating that TIA-1 does not regulate transcript stability. Rather, the absence of TIA-1 significantly increases the proportion of TNF-alpha transcripts that associate with polysomes, suggesting that TIA-1 normally functions as a translational silencer. TIA-1 does not appear to regulate the production of interleukin 1 beta, granulocyte-macrophage colony-stimulating factor or interferon gamma, indicating that its effects are, at least partially, transcript specific. Mice lacking TIA-1 are hypersensitive to the toxic effects of LPS, indicating that this translational control pathway may regulate the organismal response to microbial stress.
Subject(s)
Membrane Proteins/metabolism , Protein Biosynthesis , Proteins , RNA-Binding Proteins/metabolism , Tumor Necrosis Factor-alpha/genetics , 3' Untranslated Regions , Animals , Cytokines/biosynthesis , Gene Expression Regulation , Macrophages, Peritoneal/immunology , Membrane Proteins/genetics , Mice , Mice, Mutant Strains , RNA-Binding Proteins/genetics , Shock, Septic/mortality , T-Cell Intracellular Antigen-1ABSTRACT
Mice homozygous for the mutant Fas gene lpr develop generalized lymphoproliferation and produce autoantibodies resembling those found in human SLE. We have previously shown that these autoantibodies are produced by B2 cells rather than B1 cells and that the autoantibody- producing B cells are intrinsically abnormal. We investigated further the lpr B cell with a large panel of antibodies to B-cell surface markers to identify phenotypic abnormalities. B cells from spleen and bone marrow of age-matched congenic mice differing only at the lpr locus were examined by flow cytometry. Two consistent phenotypic differences were identified. First, spleen cells from older lpr mice had an increase in the number and percentage of IgM+ B cells expressing low levels of CD23. Second, lpr bone marrow had decreased numbers of B220hiIgM+-syndecan-1+CD23+ B cells. All other markers tested, except the previously identified modest increase of Ia on lpr spleen cells, showed no consistent differences. B cells from gld mice showed the same phenotypic abnormalities as those from lpr. Compared to T cells, the relative paucity of cell surface marker differences between lpr and +/+ B cells suggests that B cells may have fewer regulatory mechanisms to silence autoreactive specificities. The phenotypic differences identified may provide clues to the mechanism of autoantibody production in lpr mice, while the overwhelming phenotypic similarity between lpr and +/+ B cells suggests that the major abnormality of lpr B cells may lie in their specificity, that is, in their inability to delete autoreactive subsets.
