Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When given in the presence of gamma interferon (IFN-gamma), otherwise nontoxic doses of lipopolysaccharide (LPS or endotoxin) become highly lethal for mice. The mechanisms of this synergistic toxicity are not known. We considered the possibility that an interaction between the LPS-induced NF-kappaB and IFN-gamma-induced JAK-STAT pathways at the pretranscriptional level may enhance the LPS-induced signals. To test this hypothesis, we incubated murine macrophage RAW 264.7 cells with IFN-gamma for 2 h before addition of different doses of LPS. Consistent with the synergistic induction of inducible nitric oxide synthase mRNA and nitric oxide production by a combination of LPS and IFN-gamma, IFN-gamma strongly augmented LPS-induced NF-kappaB activation and accelerated the binding of NF-kappaB to DNA to as early as 5 min. In agreement with this, IFN-gamma pretreatment promoted rapid degradation of IkappaB-alpha but not that of IkappaB-beta. Inhibition of protein synthesis during IFN-gamma treatment suppressed LPS-initiated NF-kappaB binding. A rapidly induced protein appeared to be involved in IFN-gamma priming. Preincubation of cells with antibodies to tumor necrosis factor alpha or the interleukin-1 receptor partially reduced the priming effect of IFN-gamma. In a complementary manner, LPS enhanced the activation of signal-transducing activator of transcription 1 by IFN-gamma. These data suggest novel mechanisms for the synergy between IFN-gamma and LPS by which they cross-regulate the signal-transducing molecules. Through this mechanism, IFN-gamma may transform a given dose of LPS into a lethal stimulus capable of causing sepsis. It may also serve a beneficial purpose by enabling the host to respond quickly to relatively low doses of LPS and thereby activating antibacterial defenses.
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PMID:Gamma interferon augments macrophage activation by lipopolysaccharide by two distinct mechanisms, at the signal transduction level and via an autocrine mechanism involving tumor necrosis factor alpha and interleukin-1. 986 17

Leukocytes activated by endotoxin or enterotoxins release proinflammatory cytokines, thereby contributing to the cascade of events leading to septic shock. In the present studies, we analyzed the effects of in vivo administration of a soluble immunomodulator, beta-(1,6)-branched beta-(1,3)-glucan (soluble beta-glucan), on toxin-stimulated cytokine production in monocytes and lymphocytes isolated from treated mice. In vitro stimulation of lymphocytes isolated from soluble beta-glucan-treated mice with lipopolysaccharide (LPS) resulted in enhanced production of interleukin-6 (IL-6) and suppressed production of tumor necrosis factor alpha (TNF-alpha), while stimulation of these cells with staphylococcal enterotoxin B (SEB) or toxic shock syndrome toxin 1 (TSST-1) resulted in enhanced production of gamma interferon (IFN-gamma) and suppressed production of IL-2 and TNF-alpha compared to that in cells isolated from untreated mice. In vitro stimulation of monocytes isolated from soluble beta-glucan-treated mice with LPS also resulted in suppressed TNF-alpha production, while stimulation of these cells with SEB or TSST-1 resulted in suppressed IL-6 and TNF-alpha production compared to that in cells isolated from untreated mice. Thus, the overall cytokine pattern of leukocytes from soluble beta-glucan-treated mice reflects suppressed production of proinflammatory cytokines, especially TNF-alpha. Taken together, our results suggest that treatment with soluble beta-glucan can modulate the induction cytokines during sepsis, resulting in an overall decrease in host mortality.
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PMID:Modulation of endotoxin- and enterotoxin-induced cytokine release by in vivo treatment with beta-(1,6)-branched beta-(1,3)-glucan. 986 22

Burkholderia pseudomallei, the causative agent of melioidosis, is a gram-negative bacterium capable of causing either acute lethal sepsis or chronic but eventually fatal disease in infected individuals. However, despite the clinical importance of this infection in areas where it is endemic, there is essentially no information on the mechanisms of protective immunity to the bacterium. We describe here a murine model of either acute or chronic infection with B. pseudomallei in Taylor Outbred (TO) mice which mimics many features of the human pathology. Intraperitoneal infection of TO mice at doses of >10(6) CFU resulted in acute septic shock and death within 2 days. In contrast, at lower doses mice were able to clear the inoculum from the liver and spleen over a 3- to 4-week period, but persistence of the organism at other sites resulted in a chronic infection of between 2 and 16 months duration which was eventually lethal in all of the animals tested. Resistance to acute infection with B. pseudomallei was absolutely dependent upon the production of gamma interferon (IFN-gamma) in vivo. Administration of neutralizing monoclonal antibody against IFN-gamma lowered the 50% lethal dose from >5 x 10(5) to ca. 2 CFU and was associated with 8,500- and 4,400-fold increases in the bacterial burdens in the liver and spleen, respectively, together with extensive destruction of lymphoid architecture in the latter organ within 48 h. Neutralization of either tumor necrosis factor alpha or interleukin-12 but not granulocyte-macrophage colony-stimulating factor, also increased susceptibility to infection in vivo. Together, these results provide the first evidence of a host protective mechanism against B. pseudomallei. The rapid production of IFN-gamma within the first day of infection determines whether the infection proceeds to an acute lethal outcome or becomes chronic.
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PMID:Obligatory role of gamma interferon for host survival in a murine model of infection with Burkholderia pseudomallei. 1037 44

Newborns possess an altered immune response to infection with impaired leukocyte chemotaxis and deficient production of gamma-interferon (IFN-gamma). IFN-gamma enhances neonatal leukocyte activation and movement. We proposed that IFN-gamma in conjunction with penicillin compared to penicillin therapy without IFN-gamma would increase survival from group B streptococcal sepsis in a neonatal rat model. Newborn rats were infected with 10(5) cfu of group B streptococci at 48-72 h of age and randomized to receive either serum albumin (controls), rat recombinant IFN-gamma, albumin and penicillin, or IFN-gamma and penicillin. Survival 120 h postinfection revealed: controls 5% (1/21); IFN-gamma 4% (1/24); penicillin 23% (5/22); and IFN-gamma plus penicillin 10% (2/21). Survival analysis with a lognormal parametric regression model revealed only the penicillin group to have improved survival compared to controls. Contrasting the penicillin group with the IFN-gamma plus penicillin group did not reveal a statistically significant difference by the Wald chi2 statistic (p = 0.25).
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PMID:Failure of gamma-interferon to decrease mortality from group B streptococcal sepsis in neonatal rats. 1039 98

Nitric oxide (NO) production by inducible NO synthase (iNOS) during inflammation is an essential element of antimicrobial immunity but can also contribute to host-induced tissue damage. Under conditions of bacterial sepsis, large amounts of NO are produced, causing hypotension, a critical pathological feature of septic shock. In sepsis caused by gram-positive organisms, the bacterial factors contributing to host NO production are poorly characterized. We show that a soluble toxin of Streptococcus pneumoniae, pneumolysin (Pln), is a key component initiating NO production from macrophages. In contrast to wild-type bacteria, a mutant of S. pneumoniae lacking Pln failed to elicit NO production from murine macrophages. Purified recombinant Pln induced NO production at low concentrations and independently of exogenous gamma interferon (IFN-gamma) priming of RAW 264.7 macrophages. However, IFN-gamma was essential for Pln-induced NO production, since primary macrophages from mice lacking the IFN-gamma receptor or interferon regulatory factor 1, a transcription factor essential for iNOS expression, failed to produce NO when stimulated with Pln. In addition, Pln acts as an agonist of tumor necrosis factor alpha and interleukin 6 production in macrophages. The properties of Pln, previously identified as a pore-forming hemolysin, also include a role as a general inflammatory agonist.
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PMID:Pneumolysin, a protein toxin of Streptococcus pneumoniae, induces nitric oxide production from macrophages. 1041 33

When compared to controls (n = 30), human immunodeficiency virus type-1 (HIV-1)-positive individuals, either asymptomatic (n = 10) or diagnosed with acquired immunodeficiency syndrome (AIDS) (n = 10), showed a statistically significant decrease in the percentage and absolute number of CD4 ( + ) T-lymphocyte cells (flow cytometry, Becton Dickinson FACScan; mean +/- SD of 42.6 +/- 6.9 and 948.5 +/- 393.3, 19.5 +/- 8.7 and 269.8 +/- 174.3, 4.6 +/- 4.1 and 60.1 +/- 134.3, respectively; Student's t- test, p < 0.05). However, this decrease was less marked in asymptomatic patients; in fact, the percentage and number of the above cells in this group of subjects was significantly higher than in the AIDS patients (Student's t-test, p < 0.05). However, we failed to find significant differences in the percentage of natural killer cells (NKCs; CD15 ( + ) CD56 ( + ) ) between the HIV-1-infected asymptomatic or AIDS groups of patients, or when compared with the controls (mean +/- SD of 10.4% +/- 9.4%, 14.3% +/- 9.7%, and 14.8% +/- 6.4%, respectively). Whereas either group of patients had a lower number of NKCs per microliter than the control group (mean +/- SD of 137.8 +/- 87.6, 91.1 +/- 98.3, and 331. 5 +/- 266.5, respectively), this decrease only reached statistical significance for the AIDS patients (Student's t-test, p < 0.05). Healthy controls showed statistically significantly higher NKC activity than either the HIV-1-infected asymptomatic or AIDS group of patients (K-562 target cell; mean +/- SD and range values as percentage of specific lysis of 19.1% +/- 15.6% and 2.4%-58.2%, 3.4% +/- 3.2% and less than 0.1% [non-detectable]-10.3%, and 6.4% +/- 5. 5% and less than 0.1%-19.5%, respectively; Student's t-test, p < 0. 05). Challenge of samples from the control group with either interleukin-2, alpha-interferon, or with a mixture of the calcium ionophore A23187 (Io) plus the 12-O-tetradecanoylphorbol-13-acetate ester (TPA) resulted in every case in a statistically significant increase in NKC lytic function (mean +/- SD and range values as percentage of specific lysis of 19.1% +/- 15.6% and 2.4%-58.2%, 27. 6% +/- 17.4% and less than 0.1%-56.0%, 32.1% +/- 20.9% and 2.1%-76. 4%, and 62.6% +/- 24.0% and 16.7%-95.0%, respectively; Student's t-test, p < 0.05). A similar challenge for samples from the HIV-1-positive subjects, either asymptomatic or with AIDS, resulted in most cases in an enhanced NKC activity; however, this increase in NKC lytic function reached statistical significance only for the group of Io + TPA-incubated samples (Student's t-test, p < 0.05). These results indicate that control or patient baseline NKC activity, and the response of this cellular immune function to a challenge with different immunomodulators, are phenotype-independent. They also suggest an association between HIV-1 infection and alterations in the initial mechanisms responsible for NKC activation; a similar general explanation has been suggested to account for the abnormal NKC lytic function observed in various severe pathological conditions, e.g., extensive burns, polytrauma, and sepsis. Understanding the molecular mechanism involved in regulating initial NKC activation could provide the rational basis for the design of newer pharmacological strategies to treat these conditions.
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PMID:Enhancement of natural killer cell activity in HIV-1-infected subjects by a mixture of the calcium ionophore A23187 and the phorbol ester TPA: lack of response to a similar challenge with interleukin-2 or alpha-interferon. 1042 40

The efficacy of gallium (Ga) nitrate was examined in a murine model of sepsis. Male Balb/c mice (6-8 weeks) were randomized into 3 groups: 1) vehicle-treated controls 2) mice with sepsis induced by treatment with 0.3 mg i.v. of Propionibacterium acnes followed one week later by 0.01 microg lipopolysaccharide (LPS) and 10 mg of D-galactosamine (GalN) 3) mice with sepsis injected with 45 mg/kg s.c. of gallium nitrate (calculated as elemental Ga) 24 hours prior to LPS/GalN. Two hours after LPS/GalN or vehicle, plasma concentrations of tumor necrosis factor (TNF-alpha) in groups 1, 2 and 3 were 54+/-31 (n=6), 21,390+/-5139 (n=4), and 21,909+/-943 (n=5) pg/ml, respectively. After 6 hours, plasma concentrations of gamma interferon (IFN-gamma) were <10 (n=8), 4771+/-1078 (n=6), and 1622+/-531 (n=15) pg/ml, respectively, and of nitrate/nitrite (products of nitric oxide) were 64+/-8 (n=7), 146+/-18 (n=8), and 57+/-8 (n=15) microM. At 18 hours, serum chemistries were; SGOT 171+/-46 (n=13), 10,986+/-3062 (n=7), and 1078+/-549 (n=8) IU/L; SGPT 165+/-59, 17,214+/-4340, and 2088+/-1097 IU/L; and total bilirubin 0.2+/-0.0, 0.9+/-0.4, and 0.2+/-0.0 mg/dl for groups 1, 2, and 3 respectively. Blinded histologic evaluation of livers at 18 hours revealed inflammatory infiltrate scores (x [range], 0=none, 1=minimal, 2=mild, 3=moderate, and 4=severe) of 0.1 [0-1] (n=8), 3.0 [2-4] (n=15), and 2.0 [0-3] (n=10), and necrosis scores of 0.0, 2.8 [0-4], and 0.9 [0-4]. Although Ga did not affect production of TNF-alpha, it ameliorated hepatocellular injury and protected against necrosis. Based on this model of sepsis, Ga may have a role in treating the human disease.
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PMID:Gallium nitrate suppresses the production of nitric oxide and liver damage in a murine model of LPS-induced septic shock. 1050 55

During catabolic diseases such as sepsis, inflammation, and infection, a state of growth hormone (GH) resistance develops in liver. This has been attributed in part to increased production of the proinflammatory cytokine interleukin-1beta (IL-1beta). To determine how IL-1beta induces GH resistance, we studied the acid-labile subunit (ALS) gene whose hepatic transcription is increased by GH via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. IL-1beta reduced the ability of GH to stimulate ALS mRNA in rat primary hepatocytes and ALS promoter activity in H4-II-E rat hepatoma cells. This inhibition was dependent on ALSGAS1, an element resembling a gamma-interferon activated sequence that mediates the transcriptional effects of GH. Inhibition by IL-1beta was also associated with a reduction of GH-dependent binding of STAT5 to this element after chronic (8 and 24 h), but not after acute treatment (15 min). Because these results indicated that the inhibition by IL-1beta was indirect, expression of the recently discovered suppressors of cytokine action (SOCS) was examined in liver cells. IL-1beta did not alter the expression of SOCS1, SOCS2, and CIS, indicating that they are not involved. In contrast, IL-1beta increased SOCS3 mRNA by 8-fold after 24 h of treatment, whereas GH had no effect. Forced expression of SOCS3 was just as effective as IL-1beta in reducing the GH induction of ALS promoter activity in H4-II-E rat hepatoma cells. Similar results were observed in primary rat hepatocytes. We conclude that the induction of SOCS3 by IL-1beta contributes to the development of GH resistance in liver, and represents a mechanism by which cytokines such as IL-1beta cross-talk with cytokines using the JAK-STAT pathway.
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PMID:Role of the suppressor of cytokine signaling-3 in mediating the inhibitory effects of interleukin-1beta on the growth hormone-dependent transcription of the acid-labile subunit gene in liver cells. 1066 May 35

The protein product of the Toll-like receptor (TLR) 4 gene has been implicated in the signal transduction events induced by lipopolysaccharide (LPS). In mice, destructive mutations of Tlr4 impede the normal response to LPS and cause a high susceptibility to Gram-negative infection. Expression of TLR4 mRNA in humans is restricted to a small number of cell types, including LPS-responsive myeloid cells, B-cells, and endothelial cells. To investigate the molecular basis for TLR4 expression in cells of myeloid origin, we cloned the human TLR4 gene and analyzed its putative 5'-proximal promoter. In transient transfections a region of only 75 base pairs upstream of the major transcription initiation site was sufficient to induce maximal luciferase activity in THP-1 cells. The sequence of this region is similar in human and mouse TLR4 genes and lacks a TATA box, typical Sp1-sites or CCAAT box sequences. Instead, it contains consensus-binding sites for Ets family transcription factors, octamer-binding factors, and a composite interferon response factor/Ets motif. The activity of the promoter in macrophages was strictly dependent on the integrity of both half sites of the composite interferon response factor/Ets motif, which was constitutively bound by the myeloid and B-cell-specific transcription factor PU.1 and interferon consensus sequence-binding protein. These results indicate that the two tissue-restricted transcription factors PU.1 and interferon consensus sequence-binding protein participate in the basal regulation of human TLR4 in myeloid cells. Cloning of the human TLR4 gene provides a basis for further investigation of the possible impact of genetic variations on the susceptibility to infection and sepsis.
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PMID:PU.1 and interferon consensus sequence-binding protein regulate the myeloid expression of the human Toll-like receptor 4 gene. 1073 31

We summarize clinical, laboratory and pathologic details regarding a patient who presented with extrahepatic disease manifestations of hepatitis C virus (HCV) infection, including cryoglobulinemic leg ulcers due to cutaneous vasculitis, peripheral sensorimotor neuropathy, and recurrent pulmonary infiltrates. The patient had evidence for B-cell lymphoproliferation, diagnosed as extranodal lymphoma on initial (though not subsequent) bone marrow examination, retroperitoneal lymphadenopathy, and the presence of a Type II IgM6 monoclonal rheumatoid factor which became cryoprecipitable on complexing to IgG. Chronic hepatitis was mild on liver biopsy, though fibrotic changes developed over a three-year period of follow-up. She had consistently normal liver function tests, except for a brief rebound effect on discontinuing interferon-alpha, and preterminally. Symptoms were only partially responsive to trials of corticosteroids, cytotoxic agents, plasmapheresis and interferon, and the patient ultimately died at The Mount Sinai Hospital of sepsis. We review current information regarding the spectrum of extrahepatic HCV infection, including pathogenic factors relevant to its overlapping autoimmune, rheumatic and lymphoproliferative disease manifestations. The exact prevalence of these HCV-related syndromes among the 1% of the world population estimated to be infected by this virus remains to be delineated. Chronicity of infection, and lack of efficacy of currently available therapy in effecting sustained clearance of the virus from the host, have made this an important public health problem that is likely to increase in significance. Possible relationships to non-Hodgkin's lymphoma may present novel opportunities to delineate the basis for oncogenesis in HCV infection.
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PMID:Hepatitis C virus, autoimmunity and lymphoproliferation. 1074 67


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