Abstract
Challenge with low doses of LPS together with D-galactosamine causes severe liver injury, resulting in lethal shock (low dose LPS-induced shock). We examined the role of LFA-1 in low dose LPS-induced shock. LFA-1(-/-) mice were more resistant to low dose LPS-induced shock/liver injury than their heterozygous littermates, although serum levels of TNF-alpha and IL-12 were higher in these mice. C57BL/6 mice were not rescued from lethal effects of LPS by depletion of NK1(+) cells, granulocytes, or macrophages, and susceptibility of NKT cell-deficient mice was comparable to that of controls. High numbers of platelets were detected in the liver of LFA-1(+/-) mice after low dose LPS challenge, whereas liver accumulation of platelets was only marginal in LFA-1(-/-) mice. Following low dose LPS challenge, serum levels of IL-10 were higher in LFA-1(-/-) mice than in LFA-1(+/-) mice, and susceptibility to low dose LPS-induced shock as well as platelet accumulation in the liver of LFA-1(-/-) mice were markedly increased by IL-10 neutralization. Serum levels of IL-10 in LFA-1(+/-) mice were only marginally affected by macrophage depletion. However, in LFA-1(-/-) mice macrophage depletion markedly reduced serum levels of IL-10, and as a corollary, susceptibility of LFA-1(-/-) mice to low dose LPS-induced shock was markedly elevated despite the fact that TNF-alpha levels were also diminished. We conclude that LFA-1 participates in LPS-induced lethal shock/liver injury by regulating IL-10 secretion from macrophages and that IL-10 plays a decisive role in resistance to shock/liver injury. Our data point to a novel role of LFA-1 in control of the proinflammatory/anti-inflammatory cytokine network.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / administration & dosage
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Clodronic Acid / administration & dosage
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Cytokines / biosynthesis
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Cytokines / metabolism*
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Dose-Response Relationship, Immunologic
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Down-Regulation / genetics
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Down-Regulation / immunology
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Female
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Granulocytes / immunology
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Granulocytes / metabolism
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Immunity, Innate / genetics
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Inflammation Mediators / antagonists & inhibitors
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Inflammation Mediators / metabolism*
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Injections, Intravenous
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Interleukin-10 / blood
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Interleukin-10 / immunology
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Interleukin-10 / metabolism
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Interleukin-10 / physiology*
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Interleukin-12 / blood
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Interleukin-12 / physiology*
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Killer Cells, Natural / immunology
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Killer Cells, Natural / metabolism
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Leukocytosis / genetics
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Leukocytosis / immunology
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Leukocytosis / pathology
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Lipopolysaccharides / administration & dosage*
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Liver / immunology
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Liver / metabolism
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Liver / pathology*
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Lymphocyte Function-Associated Antigen-1 / genetics*
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Lymphocyte Function-Associated Antigen-1 / physiology
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Macrophages / drug effects
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Macrophages / immunology
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Macrophages / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Platelet Count
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Receptors, Antigen, T-Cell, alpha-beta / biosynthesis
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Shock, Septic / genetics
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Shock, Septic / immunology*
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Shock, Septic / mortality
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Shock, Septic / pathology
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Necrosis Factor-alpha / physiology*
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Up-Regulation / genetics
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Up-Regulation / immunology
Substances
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Antibodies, Monoclonal
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Cytokines
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Inflammation Mediators
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Lipopolysaccharides
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Lymphocyte Function-Associated Antigen-1
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Receptors, Antigen, T-Cell, alpha-beta
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Tumor Necrosis Factor-alpha
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Clodronic Acid
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Interleukin-10
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Interleukin-12