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.

Toll-like receptor 4 (TLR-4) is a critical mediator of the cellular response to lipopolysaccharide. Our purpose was to examine the role of TLR-4 in parturition and in the regulation of expression of prostaglandin synthase (cyclooxygenase [COX]-1 and COX-2) and 15-hydroxyprostaglandin dehydrogenase (PGDH) following exposure to heat-killed Escherichia coli (HKE) in pregnant mice. Inbred TLR-4-mutant C3H/HeJ mice and inbred normal C3HeB/FeJ mice on Day 14.5 of a 19- to 20-day gestation received intrauterine injection of either HKE or sterile vehicle (PBS). Preterm or term delivery was recorded for these animals. Tissues (myometrium, decidual caps, placentas, fetal membranes, and fetuses) were collected after injection of sterile vehicle or 5 x 109 HKE bacteria (n = 5 mice per strain per treatment per time point). The COX-1, COX-2, and PGDH gene expression was determined by semiquantitative reverse transcription-polymerase chain reaction. We found that 5 x 109 HKE induced preterm delivery in 100% of TLR-4-normal mice but in 0% of TLR-4-mutant mice. The HKE exposure up-regulated expression of COX-2, but not of COX-1, in maternal tissues in both mouse strains. The prostaglandin-catabolizing enzyme PGDH was down-regulated in myometrium, fetal membranes, and fetuses in control mice, but no change was observed in TLR-4-mutant mice after HKE treatment. These results demonstrate that a functional TLR-4 is essential for HKE-induced preterm labor and PGDH down-regulation but is not essential for HKE-induced COX-2 gene up-regulation. The TLR-4 may mediate bacterially induced preterm labor via regulation of prostaglandin degradation rather than prostaglandin synthesis.

The objective of this study is to test whether the activation of toll-like receptors (TLRs) 2 and 3 (innate immune receptors for gram-positive and viral pathogens, respectively) can induce preterm delivery. One uterine horn of preterm pregnant CD-1 mice at approximately 75% of gestation was injected with TLR-2 ligands (lipoteichoic acid [LTA] or peptidoglycan [PGN]) or the TLR-3 ligand polyinosinic:cytidylic acid (poly[I:C]). Preterm delivery was recorded. In a separate group of mice, tissue mRNAs were quantified by reverse transcriptase polymerase chain reaction 5 hours after treatment with PGN or poly(I:C). Intrauterine PGN and LTA induced preterm delivery, reaching 100% at maximal doses. Intraperitoneal PGN also induced preterm delivery but at lower rates (maximum = 55%). Intrauterine poly(I:C) induced preterm birth in up to 31% of mice. Poly(I:C) induced uterine interferon beta and chemokine (C-C motif) ligand 5 (CCL5, also known as RANTES) but not interleukin 1beta, tumor necrosis factor, or lipopolysaccharide-induced CXC chemokine. PGN did not alter these mRNAs when compared with saline. Neither treatment induced gene expression in fetal membranes. Activation of either TLR-2 or -3 can induce preterm delivery in the mouse. Activation of TLR-3 with poly(I:C) induces interferon beta and the chemokine CCL5 in uterine tissues but not in fetal membranes.

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Premature delivery, the most important problem in obstetrics in developed countries, continues to vex clinicians and researchers. Despite decades of investigation, the pathophysiology of premature labor is incompletely understood, and therapies or preventive strategies tailored to each of the many potential causes do not exist. The present review addresses one cause of prematurity, namely, intrauterine bacterial infection. Given the vastness of the literature for even this single etiology, we focus on the mouse as a model organism from which much can be learned about mammalian parturition. The underpinnings of bacterially induced labor are believed to involve a signaling cascade that begins with recognition of offending pathogens by cell-surface receptors (toll-like receptors). This cascade then operates through multiple branching and redundant pathways to bring about the changes within the gestational compartment that produce cervical ripening, labor, and ultimately delivery. The major challenge facing researchers is to understand the levels of complexity in the host response, so that prevention and treatment strategies may be sufficiently focused to minimize unwanted side effects, yet sufficiently broad to be effective. Given the complexity of the problem, this understanding can be aided by efficient model systems, of which one in vivo example is the mouse, an organism that shares with humans many similarities in the biochemical and molecular aspects of inflammation-induced preterm labor. We propose that tools with the power to assess simultaneously the myriad elements of the hypothesized signaling cascade (ie, genomic and proteomic technologies) are important components of the solution to the puzzle of parturition.

Inflammatory cytokines have been linked to atherosclerosis by using cell culture models and acute inflammation in animals. The goal of this study was to examine lipoprotein levels and early atherosclerosis in chronic animal models of altered IL-1 physiology by using mice with deficient or excess IL-1 receptor antagonist (IL-1ra). IL-1ra knockout C57BL͞6J mice fed a cholesterol͞cholate diet for 3 mo had a 3-fold decrease in non-high-density lipoprotein cholesterol and a trend toward increased foam-cell lesion area compared to wild-type littermate controls. IL-1ra transgenic͞low-density lipoprotein receptor (LDLR) knockout mice fed a cholesterol-saturated fat diet for 10 wk showed a 40% increase in nonhigh-density lipoprotein cholesterol, consistent with the IL-1ra knockout data, although there was no change in lesion size. When these IL1-ra overexpressing transgenic mice on the LDLR knockout background were fed a high-cholesterol͞high-fat diet containing cholate, however, a statistically significant 40% decrease in lesion area was observed compared to LDLR knockout mice lacking the transgene. By immunohistochemistry, IL-1ra was present in C57BL͞6J and LDLR knockout aortae, absent in IL-1ra knockout aortae, and present at high levels in LDLR knockout͞IL-1ra transgene aortae. In summary, IL-1ra tended to increase plasma lipoprotein levels and, when fed a cholate-containing diet, decrease foam-cell lesion size. These data demonstrate that in selected models of murine atherosclerosis, chronic IL-1ra depletion or overexpression has potentially important effects on lipoprotein metabolism and foam-cell lesion development.