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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monocyte/T-cell interactions play a critical role in the systemic response to infection. Distinct patterns of cytokines are produced by two different types of T-helper cells (Th). Th1 cells secrete interleukin-2 (IL-2) and interferon-gamma (IFN-gamma), whereas Th2 cells produce IL-4, IL-5, IL-6, IL-10, and IL-13. In volunteers systemic endotoxin administration initiates many features of gram-negative sepsis including cytokine release, but the patterns (i.e., Th1/Th2 patterns) have not yet been studied. In this institutional review board-approved study we investigated the effect of an intravenous bolus of endotoxin from Escherichia coli (4 ng/kg body weight) on the Th1/Th2 response in four female and four male volunteers (mean age 27.1 +/- 0.8 years). Plasma cytokine levels for IL-2, IL-4, IL-10, IL-12, and IFN-gamma and heart rate, mean arterial pressure, temperature, white blood cell, and differential blood count were determined before and hourly for 5 hours after endotoxin administration. All volunteers had tachycardia, decreased mean arterial pressure, fever, and leukocytosis. IL-10 was significantly (p < 0.05) elevated (9.4 +/- 3.9 pg/ml vs 60.9 +/- 19.3 pg/ml) 3 hours after endotoxin was administered, whereas IL-2 levels were decreased (69 +/- 26 U/ml vs 30.6 +/- 14.9 U/ml). IL-4 and IFN-gamma were not detectable in plasma. No changes were seen in the plasma levels of IL-12. Systemic responses did not correlate with changes in cytokine levels. Cytokine patterns found in this study suggest that after low-dose endotoxin administration the T-cell immune response is shifted towards the Th2 cell type response. This early shift towards a Th2 cell response may contribute to the depressed cell-mediated immune response associated with sepsis.
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PMID:The 1996 Moyer Award. Effects of endotoxin on the Th1/Th2 response in humans. 895 35

Cytokines serve to initiate the acute inflammatory response and to integrate nonspecific and specific immunological responses to infections occurring in perioperative patients. Microbial substances induce macrophages to produce pivotal cytokines (TNF-alpha and IL-1 beta). This results in an activation of other cytokine productions including IL-2, IL-3, IL-4, IL-6, chemokines, and IL-10. Also, other host-originated humoral mediators are released from macrophages, neutrophils, platelets, and endothelial cells Various cytokines are also produced by helper-T (Th) cells, and the Th1/Th2 balance is regulated by cytokines and stress hormones. This nonspecific inflammatory response and specific immunological response which are mediated by cytokines are crucial for the host defense against invading pathogens. On the other hand, the blood levels of TNF-alpha, IL-6, IL-8, and MIP-1 alpha were correlated with the severity and mortality in patients with sepsis. Also we found that in patients with inhalation injury the high IL-8 levels in bronchoalveolar lavage fluid on admission predicted the development of respiratory insufficiency. In severe infection, a systemic release of various cytokines is not properly regulated, and the high blood levels of the proinflammatory cytokines cause an autodestructive systemic inflammatory response syndrome (SIRS). This condition is termed "Cytokine Storm" by the author. In cytokine storm, not only proinflamamtory cytokines, but also anti-inflammatory cytokines appear in circulating blood, leading to septic shock, multiple organ dysfunction, and immunosuppression. With further understanding of the roles of cytokines in sepsis, modulation of cytokine responses could be a new modality of the treatment.
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PMID:[Cytokine-mediated biological response to severe infections in surgical patients]. 903 81

Cytokine aberrations may contribute to sepsis-associated mortality after trauma. We have previously documented that IL-10 (a Th-2 cytokine) is downregulated after tissue trauma, and the administration of exogenous IL-10 improved survival and anti-IL-10 antibody increased lethality in a murine injury-lethal endotox-emia model. IL-4 activates the Th-2 subset of T cells, and functions in a paracrine manner to inhibit proinflammatory cytokine synthesis. The purpose of this study was to investigate the kinetics of IL-4 production in this murine trauma-sepsis model. Mice (n = 50) were randomized to five groups: Control, Femur Fracture (FFx), FFx-lipopolysaccharide (LPS), FFx-LPS-IL10, and FFx-LPS-Anti-IL10. LPS (400 micrograms ip) was administered 4 days after FFx to induce lethal sepsis. IL-10 (0.5 microgram ip) or anti-IL-10 (100 micrograms IP) was administered at resuscitation, 30 min after LPS. IL-4 production was measured in ex vivo splenocyte culture supernatants at 24-hr intervals. Splenocyte IL-4 production was significantly upregulated in the FFx-LPS group that received anti-IL-10; maximal IL-4 production was on Day 5, with a greater than sevenfold increase compared to all other groups. A transient early rise in IL-4 production was noted in the FFx-LPS group that received exogenous IL-10; however, a subsequent rapid decline was documented. Treatment with anti-IL-10 antibody after FFx injury and septic challenge with LPS is associated with an upregulation of splenocyte IL-4 synthesis, as well as an increase in mortality in this murine model. IL-4 and IL-10 interaction postinjury may profoundly influence monocyte activation, cell-mediated immunity, and the subsequent host immune response to infection.
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PMID:Kinetics of splenocyte interleukin-4 production after injury and lethal endotoxin challenge. 907 Jan 78

Distinct cytokine profiles are clearly associated with and relate to the severity of several types of infections. Cytokine networks are apparent with selected human infectious diseases, such as mycobacterial infections (leprosy, tuberculosis), the parasitic infection leishmaniasis, human immunodeficiency virus (HIV) infection, and gram-negative sepsis. Cytokine profiles are determined to some extent by two functional subsets of T lymphocytes, Th1 and Th2. The Th1 cytokines (interferon gamma, interleukin-2 [IL-2], IL-12) enhance cell-mediated immunity, inhibit humoral immunity, and result in protective effect for pathogens that are removed primarily through cell-mediated immunity (Mycobacterium tuberculosis, Mycobacterium leprae, Leishmania). The Th2 cytokines (IL-4, IL-5, IL-10, IL-13) enhance humoral immunity and inhibit cell-mediated immunity, and result in protective effect for pathogens removed primarily through humoral mechanisms. Progression of HIV infection is associated with a switch from a Th1 to a Th2 profile. For sepsis, uncontrolled activation of proinflammatory cytokines (IL-1, tumor necrosis factor-alpha, interferon-gamma) may be a fundamental defect that promotes the detrimental aspects of inflammation, whereas Th2 cytokines may be beneficial in controlling inflammation. Knowledge of basic cytokine immunopharmacology, networks, and relationships with infectious processes will aid clinicians in determining treatment approaches that are likely to be effective.
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PMID:Cytokine networks with infection: mycobacterial infections, leishmaniasis, human immunodeficiency virus infection, and sepsis. 908 11

Altered host defense mechanisms after major surgery or trauma are considered important for the development of infectious complications and sepsis. In the present study, we demonstrate that major surgery results in a severe defect of T-lymphocyte proliferation and cytokine secretion in response to coligation of the antigen receptor complex and CD28. During the early postoperative course, reduced cytokine secretion was observed for interleukin-2 (IL-2), gamma interferon, and tumor necrosis factor alpha, which are associated with the Th1 phenotype of helper T lymphocytes, and for IL-4, the index cytokine of Th2 cells. During the late postoperative course, T-cell cytokine secretion increased to normal levels. Production of the anti-inflammatory cytokine IL-10 was altered, with different kinetics being selectively elevated during the late postoperative course. In contrast, the capacity of peripheral blood monocytes to present bacterial superantigens and to stimulate T-cell proliferation was normal or enhanced after surgery despite a significant loss of cell surface HLA-DR molecules. Thus, the level of major histocompatibility complex class II protein expression does not appear to predict the antigen-presenting capacity of monocytes obtained from surgical patients with uneventful postoperative recovery. Secretion of IL-1beta and IL-10 by endotoxin-stimulated peripheral blood monocytes was increased at different time points after surgery. Major surgery therefore results in a distinct pattern of immune defects with a predominant defect in the T-cell response to T-cell receptor- and CD28 coreceptor-mediated signals rather than an impaired monocyte antigen-presenting capacity. Suppression of T-cell effector functions during the early phase of the postoperative course may define a state of impaired defense against pathogens and increased susceptibility to infection and septic complications.
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PMID:Distinct mechanisms of immunosuppression as a consequence of major surgery. 916 65

Following trauma, there is an increase of Th2 cytokines (IL-4, IL-6, and IL-10) and a decrease in Th1 cytokines (IFN-gamma and IL-2) that may account for impaired cellular immunity. However, the functional significance of a dominant Th2 pattern to the host remains unclear. The aim of this study was to evaluate whether Candida albicans (CA) sepsis in the setting of a Th2 response to trauma leads to increased mortality and to examine the mediators involved. Female BALB/c mice were randomized (12 per group) to receive no injury (C); trauma, consisting of a combined femur fracture and 40% total blood loss (T); no injury plus CA infection (C+CA); and CA infection 1 week following trauma (T+CA). Survival was then followed for 3 weeks. In a separate study, mice were treated as above (5 per group) and sacrificed. Harvested splenocytes were evaluated for concanavalin A-stimulated cytokine production and liver and kidney homogenates were plated to evaluate CA growth per organ and examined histologically. Candida infection at 1 week following trauma resulted in significantly increased mortality compared to infected controls. Furthermore, the Th2 dominant cytokine pattern was significantly augmented in the presence of CA infection in both C+CA and T+CA groups. Additional analysis showed significant growth of CA in liver and kidney homogenates from T+CA compared to C+CA mice. These results suggest that injured and infected mice demonstrate augmentation of Th2 dominant responses above that of injury or infection alone, as well as a decreased ability to clear Candida which may partially explain the increase in mortality observed. Therapies designed to neutralize Th2 cytokines or augment Th1 cytokines may prove beneficial in the setting of sepsis following trauma.
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PMID:Candida infection following severe trauma exacerbates Th2 cytokines and increases mortality. 922 14

We measured the plasma levels of anti-inflammatory cytokines, including interleukin 1 receptor antagonist (IL-1ra), IL-4 and IL-10; inflammatory cytokines, including IL-2, IL-6, IL-8 and tumor necrosis factor receptor I and II (TNFR I and TNFR II); and endotoxin in 11 patients with septic shock associated with gram-negative bacteria and 12 patients with sepsis not associated with shock. The plasma levels of IL-1ra and IL-10 were elevated in the septic shock group compared with the sepsis group. TNFR I and TNFR II levels tend to be higher in the septic shock group. The plasma level of TRNF-alpha was significantly correlated with levels of IL-1ra, IL-4, IL-10, TNFR I, and TNFR II. The elevated levels of the anti-inflammatory cytokines, TNFR I, and TNFR II, appeared to reflect an attempt to suppress the shock syndrome.
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PMID:Anti-inflammatory cytokine levels in patients with septic shock. 943 13

Lack of IL-4 has been shown to be protective in some experimental models of infectious diseases in mice such as cutaneous leishmaniasis. At the same time IL-4, together with other Th2 cytokines, including IL-10 and IL-13, is known as an anti-inflammatory cytokine with the potential to down-regulate proinflammatory cytokine production. To investigate the role of IL-4 in experimental Staphylococcus aureus-induced and T lymphocyte-mediated arthritis, IL-4-deficient C57BL/6 mice (IL-4(-/-)) and their congenic controls (IL-4(+/+)) were inoculated with a toxic shock syndrome toxin-1-producing S. aureus strain. In IL-4(+/+) mice, arthritis peaked 14 days after bacterial inoculation, whereas, at that time, IL-4(-/-) mice displayed significantly less frequent (p < 0.05) joint inflammation. Paralleling lower frequency of arthritis, IL-4-deficient mice showed a decreased bacterial burden in joints (p = 0.014) and kidneys (p = 0.029), as well as lower infection-triggered weight decrease and mortality. In vitro, IL-4 inhibited intracellular killing of S. aureus in infected macrophages, without affecting phagocytosis. This finding may explain the enhanced staphylococcal clearance observed in IL-4(-/-) mice in vivo. Our results suggest that IL-4 and IL-4-dependent Th2 responses promote septic arthritis and sepsis-related mortality by inhibition of bacterial clearance during S. aureus infection.
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PMID:Staphylococcus aureus-induced septic arthritis and septic death is decreased in IL-4-deficient mice: role of IL-4 as promoter for bacterial growth. 959 Feb 59

Disruption of the IL-4 gene in two inbred mouse strains revealed a dual role of IL-4 in Staphylococcus aureus sepsis and arthritis depending on the host's genetic background. IL-4 was protective in 129SV mice, since 5 days after S. aureus inoculation IL-4(-/-) mice displayed 70% mortality as compared to survival of all 129SV wild-type counterparts. On the other hand, IL-4 was detrimental in C57BL/6 mice, since survival of IL-4(-/-) C57BL/6 mice was increased, as compared to wild-type controls, due to decreased staphylococcal growth. Altogether, our results show the dual role of IL-4 in S. aureus sepsis and arthritis, depending on the genetic background of the host.
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PMID:Outcome of Staphylococcus aureus-triggered sepsis and arthritis in IL-4-deficient mice depends on the genetic background of the host. 1045 52

Reduced cytokine production in ex vivo cultures has been regularly reported in patients suffering from sepsis syndrome. Using whole blood assays, we have now demonstrated that in sepsis patients, normal production of IL-8 was achieved with the higher concentration of lipopolysaccharide (LPS; 1 microg/ml) and with heat-killed streptococci, whereas the IL-8 production induced by lower LPS concentration (0.1 microg/ml) was significantly reduced as compared to healthy controls. In contrast, in patients undergoing cardiac surgery associated with cardio-pulmonary bypass, a group of patients with inflammation in the absence of infectious insult, none of the studied IL-8 productions were affected. Among the various anti-inflammatory cytokines known to regulate IL-8 production which we tested (i.e. IL-4, IL-10, IL-13, TGF-beta), IL-10 was the most active inhibitory cytokine in whole blood assays performed with blood samples from healthy subjects. However, its activity was not influenced by the amounts of LPS used. In addition, IL-10 also inhibited the heat-killed streptococci-induced IL-8 production and was the only cytokine to inhibit the release of IL-8 when TNF was added to LPS. It is worth noting that IL-13 which also inhibited the heat-killed streptococci-induced IL-8 production, failed to do so when the TNF production was analysed. Together, these data suggest that while circulating IL-10 in septic patients may be responsible for the hyporeactivity of circulating leukocytes, its presence is not sufficient to explain the observed dysregulation which occurs in septic patients.
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PMID:Interleukin 8 production in whole blood assays: Is interleukin 10 responsible for the downregulation observed in sepsis? 1062 43


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