Increased Resistance of LFA-1-Deficient Mice to Lipopolysaccharide-Induced Shock/Liver Injury in the Presence of TNF-α 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

摘要

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-α 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-α 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.