Counterinflammatory Cytokine Research Articles

LUMPY SKIN DISEASE VIRUS: APPROACHES TO ATTENUATION FOR VACCINE DEVELOPMENT

Lumpy skin disease (LSD) is a disease caused by the lumpy skin disease virus (LSDV) of the genus capripoxvirus. The disease is responsible for serious losses to the cattle industry globally. Vaccination is the most effective way of controlling LSDV. The currently available live attenuated vaccines are used in many countries and provide stable immunity. However, use of these vaccines can sometimes cause postvaccinal complications in animals. Attenuation of viruses by the classical method is associated with random mutations in the genome, and some vaccines can contain a mixture of viruses of different genotypes and virulence. Hence, there is a need to develop a safe immunogenic vaccine that will provide improved protection against LSDV. The most promising approach is gene modification to develop an attenuated capripoxvirus strain with high immunogenicity and protectivity. Sequencing and analysis of capripoxvirus DNA genomes has resulted in the identification of a number of genes whose protein products effectively stimulate antibody production in the host organism. These proteins are able to function both inside and outside the cell, neutralizing the complement factors, inhibiting apoptosis and synthesis of interferons, and reducing counter-inflammatory cytokines and chemokines. Here, we review the literature for instances of genetic manipulation of genes encoding the above proteins, resulting in capripoxvirus attenuation.

Toxoplasma gondii TgIST co-opts host chromatin repressors dampening STAT1-dependent gene regulation and IFN-γ-mediated host defenses.

An early hallmark of Toxoplasma gondii infection is the rapid control of the parasite population by a potent multifaceted innate immune response that engages resident and homing immune cells along with pro- and counter-inflammatory cytokines. In this context, IFN-γ activates a variety of T. gondii-targeting activities in immune and nonimmune cells but can also contribute to host immune pathology. T. gondii has evolved mechanisms to timely counteract the host IFN-γ defenses by interfering with the transcription of IFN-γ-stimulated genes. We now have identified TgIST (T. gondii inhibitor of STAT1 transcriptional activity) as a critical molecular switch that is secreted by intracellular parasites and traffics to the host cell nucleus where it inhibits STAT1-dependent proinflammatory gene expression. We show that TgIST not only sequesters STAT1 on dedicated loci but also promotes shaping of a nonpermissive chromatin through its capacity to recruit the nucleosome remodeling deacetylase (NuRD) transcriptional repressor. We found that during mice acute infection, TgIST-deficient parasites are rapidly eliminated by the homing Gr1(+) inflammatory monocytes, thus highlighting the protective role of TgIST against IFN-γ-mediated killing. By uncovering TgIST functions, this study brings novel evidence on how T. gondii has devised a molecular weapon of choice to take control over a ubiquitous immune gene expression mechanism in metazoans, as a way to promote long-term parasitism.

Central Nervous System Parasitosis and Neuroinflammation Ameliorated by Systemic IL-10 Administration in Trypanosoma brucei-Infected Mice.

Invasion of the central nervous system (CNS) by African trypanosomes represents a critical step in the development of human African trypanosomiasis. In both clinical cases and experimental mouse infections it has been demonstrated that predisposition to CNS invasion is associated with a type 1 systemic inflammatory response. Using the Trypanosoma brucei brucei GVR35 experimental infection model, we demonstrate that systemic delivery of the counter-inflammatory cytokine IL-10 lowers plasma IFN-γ and TNF-α concentrations, CNS parasitosis and ameliorates neuro-inflammatory pathology and clinical symptoms of disease. The results provide evidence that CNS invasion may be susceptible to immunological attenuation.

Severity of the compensatory anti-inflammatory response determined by monocyte HLA-DR expression may assist outcome prediction in cirrhosis

To investigate variations in expression of the monocyte antigen presentation molecule HLA-DR in cirrhosis. HLA-DR expression was measured by flow cytometry in 100 patients within 48 h of admission and repeated a week later in 21 patients admitted to ICU. IL-10, TNF-α and IFN-γ secretion in response to lipopolysaccharide and recall antigens were measured by enzyme-linked immunosorbent spot (ELISPOT) assay in 12 patients (7 with clinical immunoparesis, 5 stable). HLA-DR level was 71% in stable patients, 53% with single organ dysfunction and 34% with multiple organ failure (p < 0.02). Within these groups, no significant differences in admission HLA-DR were seen between survivors and non-survivors. HLA-DR expression less than 40% predicted 90-day mortality with a specificity of 80% and sensitivity of 59% [area under the receiver operator curve (AUROC) 0.76]. HLA-DR less than 40% was an independent predictor of prognosis in multivariate analysis with a relative risk of 2.35 (p = 0.04), although sequential organ failure assessment score (SOFA) score displaced HLA-DR when included. In those admitted to intensive care failure to increase HLA-DR expression was predictive of death within 30 days (risk ratio 6.9, p = 0.007). Follow-up values predicted outcome with similar accuracy to acute physiology and chronic health evaluation II (APACHE II)/SOFA scores (AUROC 0.88). Response to endotoxin and recall antigen was characterised by an anti-inflammatory cytokine secretion profile, and was associated with impairment in recall antigen presentation capacity. HLA-DR expression less than 40% and a failure of recovery predict poor outcome in decompensated cirrhosis, but overall prognostic power remains inferior to conventional markers. Ex vivo experiments demonstrate reduced Th1 response to antigenic stimulation and an exaggerated counter-inflammatory cytokine secretion profile.

Metabolic Response to Stress in the Neonate Who Has Surgery

After completing this article, readers should be able to: 1. Describe the basic metabolic pathways involved in neonatal nutrition. 2. Describe the effect of stress on nutrition and metabolism in the neonate undergoing surgery. 3. Describe the differences in the metabolic response to stress between an adult and a neonate. Over the past 4 decades, there have been remarkable improvements in our ability to care for critically ill infants. Progress in surgical and critical care of neonates has led to improved survival rates. Our understanding of the nutritional requirements of infants continues to advance. In contrast to years past, practitioners caring for critically ill infants undergoing surgery today have various nutritional options, including specialized parenteral and enteral formulations. Although our understanding of host defense and nutritional support continues to evolve, the interplay between the immune system and metabolism is being investigated. Hence, we are improving the match between the infant’s energy expenditure and nutritional requirements. Critical to further progress is additional understanding of the metabolic response of a neonate to surgical stress. All living organisms require energy to survive. Fuel sources enter into complex metabolic cascades to form the ultimate energy substrate, adenosine triphosphate (ATP), a fuel needed to drive and maintain all physiologic systems. Under stressful conditions, intrinsic substrate mobilizes to synthesize additional energy substrate. In essence, host substrate is mobilized for the promotion of healing after injury. Cytokines, released in response to injury, drive the catabolic response to stress, but in abundance, as with the systemic inflammatory response syndrome (SIRS), cytokines are detrimental to the organism. The nutritional requirements of a neonate are significantly greater than those of an adult because not only are there requirements for substrate intake to fulfill basic metabolic needs, but there are metabolic needs to maintain rapid and continued growth and development. Furthermore, the metabolic response …

Meningoencephalitic African trypanosomiasis: Brain IL-10 and IL-6 are associated with protection from neuro-inflammatory pathology

The relationship of neuropathology to CNS inflammatory and counter-inflammatory cytokine production in African trypanosome-infected mice was studied using an infection model with a defined disease progression. The initial phase of CNS infection by trypanosomes, where only mild neuropathology is evident, was characterised by high levels of IL-10 and IL-6. In the later phase of CNS infection and in a post-drug treatment model, moderate to severe neuropathology was associated with high levels of IFN-γ and TNF-α. The relationship of these cytokines to neuropathological grade suggests that IL-10 and IL-6 protect the CNS from inflammatory pathology when parasites first enter the brain and the data reconcile previously contradictory clinical measurements of CSF cytokines in meningoencephalitic patients with post-mortem histopathology observations.

Severity of human african trypanosomiasis in East Africa is associated with geographic location, parasite genotype, and host inflammatory cytokine response profile.

The mechanisms underlying virulence in human African trypanosomiasis are poorly understood, although studies with experimental mice suggest that unregulated host inflammatory responses are associated with disease severity. We identified two trypanosomiasis foci with dramatically different disease virulence profiles. In Uganda, infections followed an acute profile with rapid progression to the late stage (meningoencephalitic infection) in the majority of patients (86.8%). In contrast, infections in Malawi were of a chronic nature, in which few patients progressed to the late stage (7.1%), despite infections of several months' duration. All infections were confirmed to be Trypanosoma brucei rhodesiense by testing for the presence of the serum resistance-associated (SRA) gene, but trypanosomes isolated from patients in Uganda or Malawi were distinguished by an SRA gene polymorphism. The two disease profiles were associated with markedly different levels of tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta) in plasma. In Uganda but not Malawi early-stage TNF-alpha was elevated, while in Malawi but not Uganda early-stage TGF-beta was elevated. Thus, rapid disease progression in Uganda is associated with TNF-alpha-mediated inflammatory pathology, whereas in the milder disease observed in Malawi this may be ameliorated by counterinflammatory cytokines. These differing host responses may result either from differing virulence phenotypes of northern and southern trypanosomes or from immune response polymorphisms in the different host populations.

Impaired induction of IL-10 expression in the lung following hemorrhagic shock.

The balance between pro- and anti-inflammatory cytokines is considered to be an important determinant of the magnitude of inflammation in a number of disease states. We previously showed that resuscitated hemorrhagic shock augmented LPS-induced release of proinflammatory molecules by alveolar macrophages (AM). In the present studies, we evaluated the expression and regulation of the counter inflammatory cytokine IL-10 in the lung using this model. We hypothesized that impaired up-regulation of IL-10 in shock/resuscitated animals might serve as a mechanism contributing to accentuated lung inflammation. In a rodent model, animals exposed to LPS alone exhibited enhanced IL-10 mRNA levels in lung tissue as well as in AM, but antecedent shock/resuscitation delayed and attenuated the LPS-induced IL-10 mRNA levels. The ability of shock to attenuate LPS-stimulated IL-10 was also seen in the protein levels. This effect correlated with an augmented expression of cytokine-induced neutrophil chemoattractant (CINC) mRNA. Shock/resuscitated animals given exogenous IL-10 had reduced proinflammatory response, as shown by decreased expression of CINC mRNA and decreased neutrophil sequestration in the lung. Shock/resuscitation plus LPS markedly reduced the transcription rate of IL-10 mRNA compared to LPS alone but did not affect IL-10 mRNA stability. Reduced IL-10 transcription was not caused solely by impaired nuclear translocation of STAT3 and Sp1/Sp3 transcription factors because LPS-induced nuclear translocation of these factors was augmented by antecedent shock. Considered together, these findings show that shock/resuscitation suppresses LPS-induced IL-10 expression by AM in the lung by inhibiting IL-10 gene transcription. Failed up-regulation of counter inflammatory cytokines may contribute to augmented organ dysfunction in trauma patients.

Hypertonic resuscitation of hemorrhagic shock upregulates the anti-inflammatory response by alveolar macrophages

Background. Resuscitated hemorrhagic shock predisposes patients to the development of acute respiratory distress syndrome (ARDS). Hypertonic saline (HTS) has been shown to inhibit immune cell activation in response to lipopolysaccharide (LPS) in vitro and to reduce lung damage when used for resuscitation of hemorrhagic shock in vivo. We hypothesize that HTS resuscitation of hemorrhagic shock may exert this anti-inflammatory effect by modulating alveolar macrophage function leading to an altered balance between the proinflammatory and the counter-inflammatory response. Methods. A 2-hit rat model of shock resuscitation was used. Alveolar macrophages were harvested by bronchoalveolar lavage (BAL), and tumor necrosis factor (TNF)-α and interleukin (IL)-10 were quantified in the cell culture supernatants by enzyme-linked immunosorbent assay (ELISA). Alternatively, 1 hour after resuscitation, animals received endotracheal LPS followed by endotracheal anti-IL-10 neutralizing antibody. Lung injury was determined by measuring BAL neutrophil counts 4 hours after LPS in vivo administration. Results. Systemic administration of HTS significantly modulates the responsiveness of alveolar macrophages. Specifically, HTS resuscitation inhibited LPS-induced TNF-α production while enhancing IL-10 release in response to LPS administered ex vivo and in vivo. Anti-IL-10 antibody in vivo partially reversed the lung protective effect of HTS resuscitation. Conclusions. HTS resuscitation exerts an immunomodulatory effect on alveolar macrophages by shifting the balance of pro- and counter-inflammatory cytokine production in favor of an anti-inflammatory response. The in vivo data suggest a causal role for HTS-induced augmented IL-10 as protective. These findings suggest a novel mechanism for the in vivo salutary effect of HTS resuscitation on lung injury after resuscitated hemorrhagic shock. (Surgery 2003;134:312-8.)

Differential local and systemic tumor necrosis factor-alpha responses to a second hit of lipopolysaccharide after hemorrhagic shock.

The immune response to subsequent stressors after traumatic hemorrhage and resuscitation (HR) may be dependent on timing and counterinflammatory cytokine expression. Our hypothesis was that the timing of the second hit would influence the immune response, and we investigated whether an early second stimulus after HR would result in worse acute lung injury. One hour after HR or sham shock (Sham), mice were given intraperitoneal (IP) injections of lipopolysaccharide (LPS) or saline (Sal). Mortality, pulmonary function (PF), bronchoalveolar lavage neutrophil infiltration, and bronchoalveolar lavage (BAL), in addition to serum interleukin (IL)-10, IL-6, and tumor necrosis factor-alpha (TNF-alpha), were assessed. HR blunted serum TNF-alpha expression to LPS (HR+LPS, 424.8 pg/mL; Sham+LPS, 2,248.8 pg/mL; p < 0.05), but primed for increased bronchoalveolar lavage TNF-alpha (HR+LPS, 259.5 pg/mL; Sham+LPS, 23.5 pg/mL; p < 0.05). Elevated serum TNF-alpha corresponded with greater bronchoalveolar lavage neutrophil infiltration (HR+LPS, 0.93%; Sham+LPS, 17.5%; p < 0.05). IL-10 expression was similar in HR and Sham. There were no significant differences in mortality or PF between HR+LPS and Sham+LPS. Priming and blunting of the LPS-induced TNF-alpha response occurred concomitantly in two-hit mice, corresponding to an altered pattern of pulmonary inflammation, but no change in PF.

Interleukin-1 receptor antagonist gene polymorphisms in carotid atherosclerosis.

Inflammation plays an important role in the development of atherosclerosis. The gene for the counterinflammatory cytokine interleukin-1 receptor antagonist (IL-1ra) is polymorphic, and high frequencies of allele 2 have been found to be associated with other inflammatory diseases. This study examined the association of allele and carrier frequencies of the IL-1ra gene with the presence of carotid atherosclerosis and plaque symptomaticity. A total of 328 subjects identified as having carotid atherosclerosis or no atherosclerosis (controls) participated. Blood was obtained for DNA determination. Frequency of allele 2 was significantly greater in patients with atherosclerosis compared with nonatherosclerotic subjects. No difference was seen between symptomatic and asymptomatic atherosclerosis patients. Noncarriage of allele 2 was associated with reduced likelihood of atherosclerosis (odds ratio [OR], 0.44; 95% CI, 0.27 to 0.71). The homozygous carrier state for allele 2 was associated with greater likelihood of atherosclerosis (unadjusted OR, 7.30; 95% CI, 2.31 to 22.94; adjusted OR, 13.78; 95% CI, 1.94 to 97.9). A gene-dose effect was detected. These data suggest that allele 2 of the IL-1ra gene represents a susceptibility factor in the development of carotid atherosclerosis. Further investigation appears warranted.

Impaired activation of mitogen-activated protein kinases after hemorrhagic shock

Background. Patients sustaining major trauma are at risk of developing organ dysfunction. We have previously shown that resuscitated hemorrhagic shock primes for increased lung injury in response to lippolysaccharide (LPS), in part by preventing upregulation of the counterinflammatory cytokine IL-10. Because the mitogen-activated protein kinase (MAPK) family is known to participate in LPS signaling, we hypothesized that altered upstream signaling through these kinases might contribute to impaired LPS-simulated IL-10 release after shock and resuscitation. Methods. Rats were bled to a mean arterial pressure of 40 mm Hg and maintained for 1 hour, then resuscitated. Alveolar macrophages were retrieved at the end of resuscitation and exposed to LPS (0.5 μg/mL). Western blotting for p38, extracellular-regulated protein kinase, and c-Jun NH2-terminal kinase was performed on whole cell lysates. In some studies, the alveolar macrophages were preincubated with the p38 inhibitor or the extracellular-regulated protein kinase inhibitor before LPS stimulation. IL-10 levels were measured by enzyme-linked immunosorbent assay. Results. LPS caused an early activation in all members of the MAPK family, whereas antecedent shock both delayed and attenuated the LPS induction. To discern whether this reduction in LPS-stimulated MAPK activation after shock might contribute to reduced IL-10, specific inhibitors were used. Inhibition of p38 MAPK completely inhibited LPS-induced IL-10 production, whereas blockade of extracellular-regulated protein kinase pathway had no effect. Conclusions. Shock resuscitation impairs LPS-induced activation of the members of the MAPK family. For the critical counterinflammatory cytokine IL-10, inhibition of p38 activation appears to contribute to the reduced levels of this cytokine in response to LPS. This study provides in vitro evidence for altered signaling through p38 MAPK, as a mechanism leading to failed upregulation of a counterinflammatory cytokine, and thus the propagation of an unrestrained proinflammatory state. Restoration of normal signaling may represent an effective strategy to reverse this effect. (Surgery 2002;132:360-4.)

Intracellular cytokine production by fetal and adult monocytes

Background/Purpose: In light of the neonate's increased susceptibility to systemic infection, the authors hypothesized that adult and fetal monocytes have different cytokine expression profiles in response to lipopolysaccharide (LPS), and interleukin (IL)-11, a counter-inflammatory cytokine. Methods: Samples of cord blood (n = 30) and adult blood (n = 30) were obtained and treated as follows: control (baseline expression), LPS exposure, and IL-11 or IL-11+LPS exposure. After incubation with a protein transport inhibitor, mononuclear cells were stained for intracellular tumor necrosis factor (TNF)-α, IL-1β, IL-6, and IL-8. Each sample was then analyzed by flow cytometry for cytokine expression. Cytokine production was measured by the percent positive as well as the fluorescence index for each cytokine. Analysis of variance (ANOVA) and Students t tests were used for statistical analysis. Results: Baseline levels of IL-8 were significantly higher for fetal monocytes (P <.0001). After LPS exposure, fetal monocytes produced less TNF-α (P =.0105) and more IL-8 (P <.0007) relative to adult cells. IL-11 treatment reduced baseline production of IL-8 in fetal and adult monocytes (P <.05). Conclusions: These results suggest that neonatal monocytes portray a different cytokine expression profile compared with adult monocytes. IL-11 treatment appears to alter the IL-8 expression of resting fetal and adult monocytes. J Pediatr Surg 36:1321-1326. Copyright © 2001 by W.B. Saunders Company.

The effect of heat on cytokine production in rat endotoxemia.

To determine whether heat stress protects the endotoxemic rat by up-regulation of the counterinflammatory cytokine interleukin (IL)-10, thereby attenuating the inflammatory response. A total of 16 rats were assigned to either the heat stress group (n = 8) or the control group (n = 8). The heat stress group was warmed to a temperature of >42 degrees C (107.6 degrees F) rectally for 10-15 mins; 20 hrs later, all rats were intubated, paralyzed, and ventilated. After jugular venous and arterial catheterization, endotoxin was given intravenously. Arterial blood was removed at 0, 2, 4, and 5 hrs for blood gases, tumor necrosis factor (TNF)-alpha, nitric oxide metabolites (NO), IL-10, and macrophage inflammatory protein (MIP)-2. The alveolar macrophages were removed, counted, and then incubated for 24 hrs. The supernatant was analyzed for TNF-alpha, NO, IL-10, and MIP-2. University research laboratory. Male Sprague-Dawley rats (n = 16). Administration of heat before endotoxin infusion. Alveolar-arterial oxygen gradient was lower in the heat stress group at 4 and 5 hrs after endotoxemia. Plasma and alveolar macrophage supernatant concentrations of TNF-alpha, NO, and IL-10 were not affected by heat. Plasma and alveolar macrophage supernatant MIP-2 concentrations were higher in endotoxemic rats receiving heat pretreatment compared with controls. Our study demonstrates that heat leads to pulmonary protection of short duration in severe endotoxemia. This protection was not mediated by plasma TNF-alpha, IL-10, or NO. Contrary to our hypothesis, pretreatment with heat increased rather than decreased the plasma MIP-2 concentration and alveolar macrophage production of MIP-2 in endotoxemia. The mechanism of heat-conferred pulmonary protection in endotoxemia remains unclear. Alveolar macrophages do not produce IL-10 in endotoxemia. The increased MIP-2 production by heated alveolar macrophages was not attributable to alterations in production of either TNF-alpha or IL-10. The significance of increased MIP-2 by endotoxin-exposed alveolar macrophages in heated rats is unknown.

Circulating Pro- and Counterinflammatory Cytokine Levels and Severity in Necrotizing Enterocolitis

To evaluate the relationship between the severity of necrotizing enterocolitis (NEC) and circulating concentrations of proinflammatory cytokines interleukin (IL)-1beta and IL-8 and counterinflammatory cytokines IL-1 receptor antagonist (IL-1ra) and IL-10. These cytokines have been associated with bowel injury or inflammation and may be released more slowly or later than previously examined cytokines. Also, to determine if any one of these cytokines will predict the eventual severity of NEC when measured at symptom onset. Serial blood samples at onset, 8, 24, 48, and 72 hours were obtained from newborn infants with predefined signs and symptoms of NEC. Normal levels were defined from weight-, gestation-, and age-matched controls. Concentrations of the four cytokines were determined by enzyme-linked immunosorbent assay and compared throughout the time period by stage of NEC, using sepsis as a co-factor. Mean concentrations of each cytokine at onset were compared with the controls. Threshold values were obtained with the best combination of high sensitivity and high specificity for defining stage 1 NEC or for diagnosing stage 3 NEC at onset. There were 12 cases of stage 1, 18 cases of stage 2, and 6 cases of stage 3 NEC included in the study, as well as 20 control infants. Concentrations of IL-8 and IL-10 were significantly higher in infants with stage 3 NEC from onset through 24 hours compared with infants with less severe NEC. At onset, concentrations of all four cytokines were significantly higher in stage 3 NEC. To identify, at onset, the infants with a final diagnosis of stage 3 NEC, an IL-1ra concentration of >130 000 pg/mL had a sensitivity of 100% and a specificity of 92%. At 8 hours, an IL-10 concentration of >250 pg/mL had a sensitivity of 100% and a specificity of 90% in identifying stage 3 NEC in infants with symptoms suggestive of NEC at onset. The severity of NEC and its systemic signs and symptoms are not due to a deficiency of counterregulatory cytokines. In fact, mean concentrations of IL-1ra in NEC are higher than what has been reported in other populations. The cytokines IL-8, IL-1ra, and IL-10 are released later or more slowly after a stimulus and may be more useful in identifying, within hours of symptom onset, which infant will develop significant NEC.

Circulating postinjury neutrophils are primed for the release of proinflammatory cytokines.

Postinjury neutrophil (PMN) priming identifies the injured patient at risk for the subsequent development of multiple organ failure (MOF). PMN priming has previously been shown to cause enhanced release of proteases and superoxide. PMNs, however, are a rich source of proinflammatory cytokines, such as interleukin (IL)-8 and tumor necrosis factor (TNF), which have been implicated in the development of MOF. PMNs also make IL-1ra, which is an anti-inflammatory cytokine that inhibits IL-1. It is our hypothesis that postinjury PMNs are primed for increased stimulated release of the proinflammatory cytokines IL-8 and TNF but not the anti-inflammatory cytokine IL-1ra. Twelve trauma patients with a mean Injury Severity Score of 24 (+/-4.6) and 10 elective surgical patients were studied. Postinjury PMNs were isolated from blood obtained at presentation (within 2 hours after injury) and 24 hours after trauma. PMNs from elective surgical patients were obtained preoperatively, immediately postoperatively, and at 24 hours. The PMNs were stimulated with platelet-activating factor (200 nM)/N-formyl-methionyl-leucyl-phenylalanine (1 micromol/L) or lipopolysaccharide (100 ng/mL) incubated for 24 hours in RPMI-1640, and release of IL-8, TNF, and IL-1ra were measured. Postinjury PMNs were primed for both platelet-activating factor/N-formyl-methionyl-leucyl-phenylalanine-stimulated and lipopolysaccharide-stimulated IL-8 and TNF release at 2 hours after injury (fourfold increase of IL-8 release and fivefold increase of TNF release), whereas elective surgical patients demonstrated no priming. In contrast, postinjury patients were not primed for increased release of the counterinflammatory cytokine IL-1ra, suggesting a specific postinjury up-regulation of IL-8 and TNF. After injury, PMNs are primed for proinflammatory cytokine release in addition to superoxide and elastase. This augmented release of IL-8 and TNF may be involved in the subsequent development of organ dysfunction and ultimately MOF.

Sepsis and cytokines: current status

Sepsis is a constellation of clinical signs and symptoms resulting from excessive systemic host inflammatory response to infection. This inflammatory response is largely mediated by cytokines, which are released into the systemic circulation. Plasma concentrations of specific cytokines, TNF alpha, IL-1 beta, IL-6 and IL-8 are frequently elevated in human sepsis and cytokine concentrations correlate with severity and outcome of sepsis. In addition to pro-inflammatory cytokines, soluble cytokine receptors, cytokine receptor antagonists and counter-inflammatory cytokines are also produced in large quantities in patients with sepsis; however, the specific role of these molecules in sepsis remains undefined. A complex interaction of cytokines and cytokine-neutralizing molecules probably determines the clinical presentation and course of sepsis. Intervening in this sequence of events to modify the host inflammatory responses may prove to be a beneficial treatment strategy for sepsis, but currently tested anticytokine therapies have been largely unsuccessful.