Increased resistance of LFA-1-deficient mice to lipopolysaccharide-induced shock/liver injury in the presence of TNF-alpha and IL-12 is mediated by IL-10: a novel role for LFA-1 in the regulation of the proinflammatory and anti-inflammatory cytokine balance.
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.
Emoto
Masashi
M
Department of Immunology and. Central Core Facility Microscopy, Max-Planck-Institute for Infection Biology, Berlin, Germany. emoto@mpiib-berlin.mpg.de
Emoto
Yoshiko
Y
Brinkmann
Volker
V
Miyamoto
Mamiko
M
Yoshizawa
Izumi
I
Stäber
Manuela
M
van Rooijen
Nico
N
Hamann
Alf
A
Kaufmann
Stefan H E
SH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D004002:Clodronic Acid / Q000008:administration & dosage; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism*; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D006098:Granulocytes / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate / Q000235:genetics; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007275:Injections, Intravenous; D016753:Interleukin-10 / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D018664:Interleukin-12 / Q000097:blood / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D007964:Leukocytosis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics* / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010976:Platelet Count; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D000911:Antibodies, Monoclonal; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016169:Lymphocyte Function-Associated Antigen-1; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014409:Tumor Necrosis Factor-alpha; D004002:Clodronic Acid; D016753:Interleukin-10; D018664:Interleukin-12