Interleukin 1 receptor antagonist (IL-ira) is a cytokine whose only known action is competitive inhibition of the binding of interleukin 1 (IL-1) to its receptor. To investigate the physiological roles of endogenously produced IL-Ira, we generated mice that either lack IL-lra or overproduce it under control of the endogenous promoter. Mice lacking IL-lra have decreased body mass compared with wild-type controls. They are more susceptible than controls to lethal endotoxemia but are less susceptible to infection with Listeria monocytogenes. Conversely, IL-lra overproducers are protected from the lethal effects of endotoxin but are more susceptible to listeriosis. Serum levels of IL-1 following an endotoxin challenge are decreased in IL-lra nulls and increased in IL-lra overproducers in comparison to controls. These data demonstrate critical roles for endogenously produced IL-lra in growth, responses to infection and inflammation, and regulation of cytokine expression.Interleukin 1 (IL-1) is a proinflammatory cytokine that participates in the response to infectious and inflammatory challenges by recruiting and activating neutrophils and macrophages, by producing fever and vascular dilation, and by inducing mediators such as IL-6, acute phase reactants, and prostaglandin E2 (reviewed in ref.
Summary Preterm labor is defined as labor that begins before 37 completed weeks of pregnancy. More than 12% of infants born in the USA are preterm. At least 40% of preterm births are associated with intrauterine infection. Toll-like receptors (TLRs) are members of a family of cell-surface proteins responsible for recognition of a diverse spectrum of bacterial, viral and fungal pathogens. TLRs initiate the host innate (i.e. non-adaptive) immune response, inducing a proinflammatory cascade involving cytokines, chemokines, prostaglandins, and other effector molecules that result in the characteristic phenomena of labor, such as uterine contractions and rupture of fetal membranes. These cascades may also be activated by mechanisms that are not primarily infectious but are accompanied by inflammatory responses. Now that the molecular mechanisms linking infection and labor have been, to a large extent, elucidated, the challenge is to identify points of overlap with non-infectious causes of labor and to find intervention strategies that can minimize the negative impact of preterm delivery.
Inflammation plays a critical role in atherogenesis, yet the mediators linking inflammation to specific atherogenic processes remain to be elucidated. One such mediator may be secretory sphingomyelinase (S-SMase), a product of the acid sphingomyelinase gene. The secretion of S-SMase by cultured endothelial cells is induced by inflammatory cytokines, and in vivo data have implicated S-SMase in subendothelial lipoprotein aggregation, macrophage foam cell formation, and possibly other atherogenic processes. Thus, the goal of this study was to seek evidence for S-SMase regulation in vivo during a physiologically relevant inflammatory response. First, wild-type mice were injected with saline or lipopolysaccharide (LPS) as a model of acute systemic inflammation. Serum S-SMase activity 3 h postinjection was increased 2-to 2.5-fold by LPS (P < 0.01). To determine the role of IL-1 in the LPS response, we used IL-1 converting enzyme knockout mice, which exhibit deficient IL-1 bioactivity. The level of serum S-SMase activity in LPS-injected IL-1 converting enzyme knockout mice was Ϸ35% less than that in identically treated wild-type mice (P < 0.01). In LPS-injected IL-1-receptor antagonist knockout mice, which have an enhanced response to IL-1, serum S-SMase activity was increased 1.8-fold compared with LPS-injected wild-type mice (P < 0.01). Finally, when wild-type mice were injected directly with IL-1, tumor necrosis factor ␣, or both, serum S-SMase activity increased 1.6-, 2.3-, and 2.9-fold, respectively (P < 0.01). These data show regulation of S-SMase activity in vivo and they raise the possibility that local stimulation of S-SMase may contribute to the effects of inflammatory cytokines in atherosclerosis.
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