Dynamics and Kinetics of Ligand Receptor Binding

As is the case for the class I cytokine receptors, ObRb probably dimerizes in order to signal optimally (66). Unlike the other receptors of this class that form heterodimers with gp130 (57), ObRb forms homodimers or homo-oligomers (67). This homo-oligomerization is ligand independent and signaling via ObRb is not susceptible to dominant negative repression by the short isoforms, even when they are present in great excess (66). The leptin receptor is able to homo-oligomerize in an...

Interleukin9

Interleukin-9 is a T-cell-derived cytokine, originally described as a growth factor for T-cells and mast cells. Prophylactic injections of IL-9 conferred resistance of mice challenged with a lethal concentration of Pseudomonas aeruginosa (241). This protective effect correlated with a marked decrease of serum levels of TNF, IL-12, and IFN-y, as well as an increase of circulating IL-10 and IL-10 mRNA expression in the spleen. Interestingly, a shorter and lower expression of IL-9 mRNA was...

Info

Studies trying to associate incidence or severity of infectious disease with TNF polymorphisms have been published on a variety of pathogens. Positive associations of the biallelic TNF -308 as well as LTa polymorphisms with susceptibility to mucocutaneous leishmaniasis and leprosy have been reported (27,28). Genotyping of this polymorphism in patients with severe sepsis or septic shock still shows controversial results. In contrast to the negative findings in sepsis are the results of two...

The obob and dbdb Mouse as a Model of Starvation

It has been suggested that the ob ob and the db db mice are models of perceived starvation, despite their obvious obesity. Given that a falling leptin concentration can be considered a signal of starvation, then mice deficient in leptin or its receptor become obese because they perceive that they are starving and thus become hyperphagic (14). Furthermore, these strains of mice share many of the other physiological and behavioral features of chronic starvation such as infertility, reduced...

Introduction

Severe sepsis represents 2.26 cases per 100 hospital discharges in the United States (1). With an estimate of 751,000 cases a year in the United States and a 28.6 mortality, severe sepsis is responsible for 9.3 of the deaths in this country (i.e., as many deaths annually as those from acute myocar-dial infarction). Although in the past, Gram-negative sepsis cases were most frequent, recent surveys suggest that around 35 of the sepsis cases are the result of Gram-negative infections (2,3)....

Contributors

Laurence Arbibe, md Unit de Biologie Mol culaire de l'Expression G nique, Institut Pasteur, Paris, France Antonio Bertoletti, md Institute of Hepatology, Royal Free University College Medical School, University College London, UK Pierre-Yves Bochud, md Division of Infectious Diseases, Department of Internal Medicine, Centre Hospital Universitaire Vaudois, Lausanne, Switzerland Thierry Calandra, md, phd Division of Infectious Diseases, Department of Internal Medicine, Centre Hospital...

Cytokine Gene Polymorphism Candidate Genes 21 Tumor Necrosis Factor

Primary proinflammatory cytokines like TNF and IL-1 induce secondary proinflammatory and anti-inflammatory mediators like IL-6 and IL-10. They have been shown to contribute substantially to the host's primary response to infection. Both TNF and IL-1 are capable of inducing the same symptoms and the same severity of septic shock and organ dysfunction as endotoxin in experimental settings as well as in humans (6). Genetic variations in the TNF and IL-1 genes are of major interest concerning...

Findings In Other Cytokine Candidate Genes

Interleukin-10 shows well-defined haplotypic promoter variation. High IL-10 secretors presenting with fever of unknown origin display an increased mortality rate (48), whereas susceptibility to severe meningococcal disease as well as poor outcome seem to be linked to inherited high IL-10 secretion and low TNF release in a family study testing ex vivo cytokine inducibility (49). IL-10 promoter genotypes could not be associated with incidence or outcome of severe abdominal sepsis (Fig. 1). In...

Conclusion

Uncovering and understanding the genetic determination of the susceptibility to infection offers the chance of developing valuable diagnostic tools and new therapeutic approaches in severe sepsis. Evaluation of candidate genomic markers for risk stratification of individuals at high risk of developing infectious disease has just begun. Many candidate genes still have to be studied and clinical significance of genomic markers will be tested. In addition, this new approach may prove to be a...

Contents

List of Introduction Cytokine Biology Relevant to Infectious 1 Leptin Its Role in Immunomodulation and Susceptibility to 2 Cytokine Gene Polymorphism and Host Susceptibility to II Cytokines in Gram-Negative Infections 3 Proinflammatory and Anti-Inflammatory Cytokines as Mediators of Gram-Negative 4 Host Response to Pathogenic Bacteria at Mucosal Laurence Arbibe and Philippe Sansonetti 5 Macrophage Migration Inhibitory Factor as a Cytokine of Innate Immunity 65 III Cytokines in Gram-Positive...

Interleukin1 Receptor Antagonist

Proinflammatory mediators comprise the hyperinflammatory side of the host's response to infection. At the same time, anti-inflammatory mediators are induced by proinflammatory cytokines and try to counterbalance the increased inflammatory activity. This physiologic process of limiting the extent of inflammation by release of anti-inflammatory proteins may escape physiologic boundaries of local and systemic concentrations of these mediators. Proteins like IL-4, IL-10, IL-11 or IL-13, or IL-1ra...

Il10592

Comparison of allele frequencies of IL-10 promoter polymorphisms in nonsurvivors (n 67) and survivors (n 63) with severe abdominal sepsis (p > 0.05). Negative associations between IL-1ra polymorphisms and susceptibility to infection have been suggested for vaginal mycoplasma colonization, cytomegalovirus and Epstein-Barr virus infection as well as human immunodeficiency virus (HIV) reproductivity and hemorrhagic fever caused by a hantavirus (see reviews in refs. 46,47).

Interferonj

The synergy of IFN-y with the detrimental activities of LPS has been clearly established IFN-y enhanced LPS-induced circulating TNF as well as LPS- and TNF-induced mortality (144,175) and anti-IFN-y antibodies protected against LPS- and E. coli-induced mortality (175,176). As a consequence, a clinically silent viral infection may induce hypersensitivity to Gram-negative bacterial endotoxin through T-cell activation and subsequent IFN-y production, leading to a hyperproduction of TNF (177). Mice...

High Mobility Group1 Protein

High mobility group-1 is a highly conserved nuclear protein that binds cruciform DNA. It exists as a membrane form and as an extracellular form that interacts with plasminogen and tissue-type plas-minogen activator. It is produced by macrophages in response to LPS and by the pituitary cell stimulated by IL-1 or TNF (200). HMG-1 was reported to be a late mediator of endotoxin lethality in mice and found in plasma of septic patients, with significantly higher levels in nonsurvivors than in...

Interleukin18

Although IL-18 promotes resolution of bacterial infection in mice (170), it accounts for both TNF and Fas-ligand-mediated hepatotoxic pathways in endotoxin-induced liver injury in this model (171). Neutralization of IL-18 protects mice against lethal E. coli and S. typhimurium endotoxemia (172), and IL-18-deficient mice showed decreased sensitivity toward LPS-induced shock (173), although this might depend on the model because Propionibacterium acnes-primed IL-18- - mice were highly susceptible...

Interleukin1

The cascade of inflammatory events is mainly orchestrated by IL-1 and TNF. Injection of IL-1 into animals results in hypotension, increased cardiac output and heart rate, leukopenia, thrombocy-topenia, hemorrhage, and pulmonary edema (143). Cyclo-oxygenase inhibitors greatly prevent these different effects. Interleukin-1 receptor antagonist (IL-1ra), a natural IL-1 inhibitor, reduces mortality from endotoxic shock (151). IL-1P- converting enzyme (ICE) or caspase-1 is the enzyme required for the...

Sources of Cytokines

Immunohistochemical Analysis Different approaches have helped to identify the sites of production of cytokines during endotoxic shock or bacterial sepsis. Immunohistochemical analysis of tissues have revealed the presence of IL-1P and TNF in the spleen, liver, lung, heart, pituitary gland, and kidney following injection of LPS or bacteria in mice (110-113). In the CLP model of peritonitis and sepsis, the presence of IL-1P and TNF in mice liver has been demonstrated by immunohistochemical...

Ex Vivo Cytokine Production by Lymphocytes

Sepsis syndrome is associated with an exacerbated in vivo production of proinflammatory and antiinflammatory cytokines as assessed by their increased levels in the blood stream. Paradoxically, a reduced capacity of circulating leukocytes from septic patients to produce cytokines has been regularly reported as compared to cells from healthy controls. The very first observation on the hyporeactivity of circulating cells in septic patients was demonstrated in peripheral blood lymphocytes Wood et...

Comparison Of Mouse And Human Responses To Bacterial Endotoxins

In critically ill patients with sepsis syndrome or septic shock, the transient overproduction of proinflammatory cytokines likely contributes to manifestation of the systemic inflammatory response, development of organ failure, and even death. In order to study the role of cytokines in sepsis, injection of purified endotoxins and exotoxins have been used to mimic Gram-negative and Gram-positive infections, respectively. In animal models of endotoxemia or exotoxemia, blocking the production and...

The Biology Of The Action Of Leptin 21 The Obese Gene and its Protein Product Leptin

In 1994, the mouse obese (ob) gene and its human homolog were isolated by positional cloning (2). In humans, the gene is positioned at 7q31. The mouse ob gene resides on chromosome 6 and consists of three exons and two introns and encodes a 4.5-kilobase (kb) mRNA. The coding sequence is contained within exons 2 and 3. The wild-type obese gene encodes a 167-amino-acid protein named leptin, expressed almost exclusively in white adipose tissue, although recently its expression has been found at...

Detection Of Cytokines In The Blood Compartment 21 Circulating Cytokines and Soluble Receptors

Tumor Necrosis Factor and Lymphotoxin-a In 1986, TNF was the first cytokine identified in the sera of patients with septicemia (16) and later in patients with meningococcal sepsis (17,18). Although a correlation between poor outcome and high levels of circulating TNF exists in the case of meningococcal sepsis (17,18), in other forms of sepsis, some authors also observe such a correlation (19,20), whereas others did not (21,22). Kinetics of plasma TNF have been reported (20,22) The...

Fas Ligand

Fas (CD95) is a member of the TNF receptor superfamily that contains a cytoplasmic death domain. Binding of FasL to Fas induces apoptosis. Fas ligand (FasL) exists as a membrane form of a soluble molecule. Sepsis is associated with a delayed apoptosis of neutrophils, but with an increased apoptosis in hematopoietic tissues such as thymus, Peyer's patch, spleen, and bone marrow. Using FasL-defi-cient mice, it was established that the sepsis-associated apoptosis of lymphoid cells was a...

Interleukin12

The injection of IL-12 in chimpanzees induces an increase in plasma concentrations of IFN-y as well as IL-15, IL-18, a- and P-chemokines, and anti-inflammatory mediators (163). Among the adverse effects of IL-12, hepatomegaly and splenomegaly, leukopenia, anemia, and myelodepression have been reported (164). These phenomena were largely IFN-y-dependent because they were not reported to occur in IFN-y-receptor-deficient mice. Hepatomegaly is associated with infiltration of activated macrophages...

Interleukin10

Interleukin-10 is a well-known cytokine that exerts its anti-inflammatory properties particularly on monocytes macrophages, neutrophils, and T-lymphocytes. IL-10 is capable of preventing lethality in experimental endotoxemia (222), and IL-10-deficient mice were far more sensitive to LPS-induced lethality than wild-type animals (223). In addition, neutralization of IL-10 in endotoxemia and during experimental septic peritonitis illustrated that endogenously produced IL-10 was instrumental in...

Macrophage Migration Inhibitory Factor

Macrophage inhibitory factor (MIF) was first discovered in 1966 as a T-cell product released during delayed-type hypersensitivity (193) and rediscovered in 1993 as a pituitary-derived cytokine that potentiates lethal endotoxemia (194) as well as a macrophage product (195) induced by the action of glucocorticoids (196). MIF is expressed constitutively in many tissues, including lung, liver, kidney, spleen, adrenal gland, and skin. MIF exists as a preformed cytokine that is rapidly released...

Polymicrobial Sepsis As A Model

Several studies have examined the role of cytokines using live infection, particularly cecal liga-tion and puncture. In this model, mice or rats undergo ligation of the cecum followed by a single or double puncture with a small or large needle. After the procedure, the peritoneal cavity is surgically closed. The rapidly evolving peritonitis varies in severity depending on the size and number of holes, but even with antibiotic treatment, death generally takes place in 2-10 d. Bacteria are found...

Starvation And Immune Responses 41 Models of Starvation in Normal Mice

Animal models have been set up to investigate the effects of food restriction on immune responses. It is important to define the terms of reference carefully when assessing the literature. Starvation is defined as withholding all food for a short defined period and allowing the animal free access to water. Following this short period of starvation, the animal is then allowed free access to food. A period of 48 h of food withdrawal is usually used in mice, because 24 h produces mild...

The Cell Mediated Immune Response in Starvation

As mentioned earlier, the cellular immune system seems particularly sensitive to undernutrition and starvation. The reasons for this are unknown and it has been hypothesized that much immunosuppression is the result of specific micronutrient deficiency. However, these deficiencies occur relatively sporadically, yet the type of immune impairment seen is fairly consistent, casting some doubt on this hypothesis. The immune phenotype seen in SII includes reduced delayed-type hypersensitiv-ity...

The Effects Of Leptin On The Immune System 51 The Innate Immune Reponse

As mentioned earlier, the pattern of leptin release during an acute-phase response mirrors other cytokine gene expression, particularly IL-6 (11-13). It has been shown that LPS, IL-1, TNF-a, and other inflammatory stimuli increase gene expression and serum concentration of leptin as early as 6 h after the initial stimulus. The induction of gene expression makes leptin an ideal candidate to be a key player in an immune inflammatory response. It is of particular interest that LPS binds to a...

Disadvantages of Using Knockout Mice

The primary disadvantage of using cytokine knockout mice is the lack of clinical relevance of absent cytokine activity in knockout mice compared to reduced cytokine activity when using anticytokine therapies. For example, the administration of any TNF inhibitor results in a peak of the inhibitor, followed by a nadir prior to the next injection. It is unlikely that complete and sustained neutralization of TNF-a occurs with current dosing. In the case of IL-1 inhibition, 24 h after an intravenous...

Tumor Necrosis Factor

Tumor necrosis factor toxicity includes hemodynamic instability, fever, diarrhea, metabolic aci-dosis, capillary leak syndrome, activation of coagulation, late hypoglycemia, induction of a catabolic state, neurotoxicity, cachexia, and renal and hematological disorders, all phenomena associated with sepsis syndrome (142). In addition, together with IL-1, TNF induces on the endothelial cell the expression of adhesion molecules involved in organ infiltration by leukocytes. The lethal effect of TNF...

Role of Leptin in the Regulation of Body Weight

Chronic administration of recombinant ob protein has been shown to produce a significant reduction in body weight in ob ob and normal mice because of a reduction in food intake but also an increase in energy expenditure (26-28). Centrally administered leptin (into the lateral or third cerebral ventricles) has been shown to be particularly effective in promoting anorexia and weight loss at doses which when administered peripherally were without effect on feeding behavior (26). This suggests that...

The Cognate Immune Response

As mentioned earlier, the innate and cognate immune systems are interlinked, so that many of the effects of leptin discussed in Section 4 will have implications for the behavior of responding lymphocytes. It is also clear that an organism mounts a coordinated immune response to an infectious pathogen that initially comprises innate immunity and then evolves, if appropriate to involve the cognate immune system. An important point of communication between the innate and cognate arms of the immune...

Role of Leptin as a Signal of Starvation

In 1996, Ahima et al. proposed a role for leptin as a signal of energy deficiency (14). Circulating leptin levels fall rapidly in response to starvation when energy intake is limited and energy stores (fat) are declining. It was suggested that leptin may have evolved to signal the shift between sufficient and insufficient energy stores (18). The hypothesis that reduced circulating leptin levels signal nutrient deprivation is supported by the demonstration that prevention of the...

In Vivo Models Of Leptin Deficiency 31 The obob and dbdb Mouse

Recessive mutations in the mouse diabetes (db) and obese (ob) genes have long been recognized to cause a syndrome of obesity and diabetes resembling morbid obesity in humans (32,72). These mice are phenotypically identical, each weighing three times more than normal mice, with a fivefold increase in body fat content. In his pioneering parabiosis work, Coleman showed that the obesity in the ob ob mouse was the result of the lack of a circulating satiety factor and that the phenotype of the db db...