Rapid diagnosis of sigmoid volvulus with water soluble urografin in emergency service.
Explore the source record for details and available documents.
Aged↗
Biomedical subjects
M T Lin
Publications and source records attributed to M T Lin.
Generation of HLA-C-specific cytotoxic T cells in association with marrow graft rejection: analysis of alloimmunity by T-cell cloning and testing of T-cell-receptor rearrangements.
Peripheral blood mononuclear cells from a patient who rejected a T-cell-depleted marrow graft showed spontaneous cytotoxic activity specific for HLA-Cw4 and HLA-B35 alloantigens of the donor. T-cell-receptor complementarity-determining region 3 length distributions in a blood sample obtained at the time of rejection generally showed distortions in only 1 or 2 peaks, indicating that recipient T cells with a broad repertoire of antigen receptors survived the pretransplantation conditioning regimen. An HLA-Cw4-specific, CD8 T-cell clone was recovered from a blood sample after rejection. The T-cell-receptor-B gene rearrangement expressed by this clone was not readily detectable in other blood samples drawn before or after the transplantation, indicating that this clone was only 1 of many recipient-derived T cells that recognized HLA alloantigens of the donor. These results demonstrate the role of the HLA-C locus in T-cell-mediated alloimmune responses and add to emerging evidence that indicates the need to evaluate HLA-C compatibility in selecting hematopoietic stem cell donors for patients who have an increased risk of rejection.
Adult↗
Association of TLR4 mutations and the risk for acute GVHD after HLA-matched-sibling hematopoietic stem cell transplantation.
Lipopolysaccharide (LPS) has been implicated in the pathogenesis of graft-versus-host disease (GVHD). The toll-like receptor (TLR)-4 has been recently identified as a major receptor for LPS. Mutations of TLR4 have been associated with LPS hyporesponsiveness. We hypothesized that TLR4 mutations reduce the risk of acute GVHD in allogeneic marrow transplant recipients. In a preliminary study to determine the frequency of TLR4 mutations and their possible association with GVHD, we tested 237 patients and their HLA-identical sibling donors for 2 TLR4 polymorphisms. All patients received methotrexate and cyclosporine for GVHD prophylaxis. One or more mutants were detected in 10.8% of patients and 10.6% of donors. Multivariable logistic regression models were used to analyze the association between TLR4 mutations and probability (1-sided) of GVHD. The odds ratio (adjusted for advanced disease, total body irradiation dose, and patient age) for development of grades II to IV GVHD when a mutation was present in the recipient was 0.63 (95% confidence interval [CI], 0.25-1.60; P = .16). When a mutation was present in the donor, the adjusted odds ratio was 0.88 (95% CI, 0.36-2.17; P = .40). When a mutation was present in both recipient and donor, the odds ratio was 0.72 (95% CI, 0.22-2.32; P = .29). Among 24 patients with TLR4 mutations in either donor or recipient, 4 (16.7%) developed gram-negative bacteremia. Among 213 patients without mutations, 14 (6.6%) developed gram-negative bacteremia (P = .09). The data indicate that a reduced risk of acute GVHD is associated with TLR4 mutations and that TLR4 mutations may increase the risk for gram-negative bacteremia. However, these associations are not statistically significant in recipients of HLA-matched sibling marrow transplants who are prophylactically treated for infections and GVHD. A much larger study population would be needed to confirm the role of LPS in the pathogenesis of GVHD in humans.
Bacteremia↗
IL-6 inhibits apoptosis and retains oxidative DNA lesions in human gastric cancer AGS cells through up-regulation of anti-apoptotic gene mcl-1.
Apoptosis plays a critical role in maintaining genomic integrity by selectively removing the most heavily damaged cells from the population. Reactive oxygen species (ROS) and certain inflammatory cytokines are always elevated during the human carcinogenic process. However, the biological significance of the interplay between ROS and inflammatory cytokine remains elusive. This study demonstrates that interleukin-6 (IL-6) effectively protects gastric cancer cells from the apoptosis induced by hydrogen peroxide (H(2)O(2)). The cell death signaling JNK pathway elicited by H(2)O(2) is also inhibited by IL-6. We further found that Mcl-1, but not other Bcl-2 family members, was up-regulated by IL-6, by a substantial level over 24 h. We further transfected a mcl-1 expression vector, pCMV-mcl-1, into the AGS cells, and successfully obtained several mcl-1-overexpressing clones. Flow cytometric analysis shows that these mcl-1-overexpressing AGS cells are more resistant to the apoptosis induced by H(2)O(2) when compared with the neo control AGS cells. Consistently, the activation of the JNK pathway induced by H(2)O(2) is also blocked in mcl-1-overexpressed cells. These results indicate that the anti-apoptotic effect of IL-6 is, at least in part, due to the up-regulation of mcl-1. To our surprise, either IL-6 exposure or mcl-1 overexpression fails to reduce the level of intracellular peroxides in the AGS cells triggered by H(2)O(2). This study also determined the level of 8-hydroxydeoxyguanosine (8-OH-dGua), an indicator for oxidative DNA lesions in IL-6-treated or mcl-1-overexpressed AGS cells after treatment with H(2)O(2). Notably, our results indicate that a majority of the 8-OH-dGua is efficiently removed in the AGS cells without IL-6 treatment, whereas only approximately 50% of the 8-OH-dGua was repaired in the IL-6-treated AGS cells after 24 h. Similarly, approximately 60-70% of the 8-OH-dGua also failed to repair and was retained in the genomic DNA of the mcl-1 transfectants. Results in this study provide a novel mechanism by which up-regulation of the Mcl-1 protein by IL-6 may enhance the susceptibility to H(2)O(2)-induced oxidative DNA lesions by overriding apoptosis.
8-Hydroxy-2'-Deoxyguanosine↗
Clinicopathologic association of cyclooxygenase 1 and cyclooxygenase 2 expression in gastric adenocarcinoma.
OBJECTIVE: To evaluate the association of clinicopathologic factors and prognostic value with the expression of cyclooxygenase 1 and 2 in patients with gastric adenocarcinoma. SUMMARY BACKGROUND DATA: Epidemiologic studies have indicated that nonsteroidal antiinflammatory drugs reduce the risk of colon cancer by as much as 40% and also decrease the risk of gastric cancer. Recently, gastric cancer was found to express constitutive cyclooxygenase 1 and inducible cyclooxygenase 2 isoenzymes. Nonsteroidal antiinflammatories, which may function as cyclooxygenase inhibitors, inhibited the growth of gastric cancer cells. These two isoenzymes' expressions associated with traditional clinicopathologic factors have not been fully evaluated, and their prognostic value for determining survival in patients remains to be clarified. METHODS: Seventy-one specimens resected from patients with gastric adenocarcinoma were investigated by immunohistochemical stain against cyclooxygenase 1 and 2. The 71 specimens were divided into stain-positive and stain-negative groups. Correlations between cyclooxygenase 1 and 2 expression, various clinicopathologic factors (including vascular invasion and Helicobacter pylori infection), and prognosis were studied. RESULTS: The cyclooxygenase 2-positive group was significantly correlated with vascular invasion and H. pylori infection by univariate and multivariate analysis. In patients with cyclooxygenase 2-positive cancer, the prognosis was significantly poorer than in those with cyclooxygenase 2-negative cancer. However, multivariate analysis showed that vascular invasion, serosal invasion, and lymph node metastasis were independent prognostic factors for patients with gastric cancer, but cyclooxygenase 2 expression was not. There was no significant correlation between cyclooxygenase 1 expression and clinicopathologic factors and prognosis. CONCLUSIONS: Upregulated cyclooxygenase 2 expression was associated with H. pylori infection in gastric cancer and was also strongly correlated with positive vascular invasion, which was an independent prognostic factor for poorer survival in this study. The usefulness of cyclooxygenase 2 inhibitors in the prevention or treatment of gastric cancer remains undetermined but deserves further investigation.
Adenocarcinoma↗
Ex vivo fluorescence microscopy provides simple and accurate assessment of neutrophil-endothelial adhesion in the rat lung.
Neutrophil adhesion to the pulmonary endothelium is prerequisite to neutrophil transmigration and activation, both of which may lead to lung injury. A simple method to evaluate neutrophil adherence in the lung would be useful for developing new strategies for neutrophil-mediated lung injury. The purpose was to establish a simple method to evaluate neutrophil adhesion in the lung using ex vivo fluorescence microscopy. Rats were anesthetized, and the right jugular veins were catheterized. Neutrophils were isolated from another set of rats and labeled with 5,(6)-carboxyfluorescein diacetate. Animals were killed 120 s after a 1 x 10(6) labeled neutrophil injection. The pulmonary labeled neutrophil number was counted under a fluorescence microscope. In the first experiment, rats were given 0, 20, 200, or 2000 microg/kg lipopolysaccharide (LPS) i.p. At 4 h after challenge, the pulmonary labeled neutrophil number was determined. Kinetic studies were also performed at 0, 1, 4, and 8 h after 200 microg/kg LPS. Finally, anti-ICAM-1 Ab was injected i.v. before LPS 200 microg/kg, and the labeled neutrophil number in the lung was determined at 4 h. The number of pulmonary labeled neutrophils was higher after LPS 200 or 2000 microg/kg than after the other doses. The pulmonary labeled neutrophil number was increased at 4 h compared with the other time points. ICAM-1 blocking normalized the pulmonary labeled neutrophil number in the LPS group. In conclusion, our method seems to reflect ICAM-1-mediated neutrophil adherence to the endothelium in the present setting. This simple technique may be useful for evaluating neutrophil adhesion.
Animals↗
The protective effect of hypervolemic hemodilution in experimental heatstroke.
The authors tested the hypothesis in a rat model that hypervolemic hemodilution during heatstroke affected the mean arterial pressure (MAP), striatal dopamine (DA) release, and local cerebral blood flow and neuronal damage score in different brain structures. The heatstroke was induced by exposing the urethane-anesthetized rats to an ambient temperature of 42 degrees C. Hypervolemic hemodilution was produced by intravenous administration of 10% human albumin. Relative and absolute blood flow in the corpus striatum were determined using the laser Doppler flowmetry and the autoradiography diffusible tracer technique, respectively. The DA release in the striatum was estimated using the in vivo microdialysis technique. After onset of heatstroke, animals with hypervolemic state alone, produced by saline or heparinized blood injection, displayed higher values of DA release, as well as neuronal damage score in the striatum, hypothalamus, or cortex, but lower values of MAP and blood flow in the striatum, hypothalamus, or cortex compared to normothermic controls. However, the heatstroke-induced arterial hypotension, cerebral ischemia, increased striatal DA overload, and increased neuronal damage score were attenuated by induction of both hypervolemic and hemodilution state with 10% albumin either before or after the onset of heatstroke. In addition, constant infusions of a vasopressor agent phenylephrine (2 microg kg(-1) min(-1)) after the onset of heatstroke failed to maintain appropriate levels of MAP and resulted in no protection against heatstroke. Thus, it appears that the observed benefit of the 10% albumin is secondary to hemodilution and/or maintenance of MAP.
Analysis of Variance↗
Immunohistochemical evaluation of cadherin and catenin expression in early gastric carcinomas: correlation with clinicopathologic characteristics and Helicobacter pylori infection.
Dysfunction of E-cadherin and catenin has been linked to invasiveness and differentiation of tumors. This study aimed to characterize the expression of cadherins and catenins in early gastric carcinoma and their relationship to clinicopathologic characteristics and Helicobacter pylori infection. E-cadherin and alpha-, beta- and gamma-catenins were strongly expressed in normal epithelium but abnormal immunoreactivity of at least one of these four proteins was noted in 48 (90.6%) of 53 early gastric carcinomas. Only 5 cases with intestinal-type tumors had intact expression of E-cadherin and alpha-, beta-, and gamma-catenins. Abnormal immunoreactivity in the tumor tissue was observed in 18 patients (34.0%) for E-cadherin, in 35 (66.0%) for alpha-catenin, in 20 (37.7%) for beta-catenin, and in 37 (69.8%) for gamma-catenin. In diffuse-type tumors, abnormal expression of E-cadherin (60.9 vs. 13.3%, p < 0.0005), alpha-catenin (82.6 vs. 53.3%, p < 0.05) and gamma-catenin (91.3 vs. 53.3%, p < 0.005) was more frequent than in the intestinal type. Ten tumors with lymph node metastasis showed a relatively higher frequency of abnormal expression of E-cadherin (70 vs. 25.6%, p < 0.05) but a lower frequency of abnormal expression of beta-catenin (10 vs. 44.1%, p = 0.07) than those without metastasis. No significant association was found between cadherin/catenin expression and the depth of invasion or the H. pylori status. It was concluded that abnormal expression of E-cadherin and the catenin-mediated cell-cell adhesion system occurs frequently in early gastric carcinogenesis and may play an important role in the genesis of histologic differentiation and in the mode of metastasis of early gastric carcinomas.
Armadillo Domain Proteins↗
Glucocorticoids reduce interleukin-1 concentration and result in neuroprotective effects in rat heatstroke.
In urethane-anaesthetized rats, we assessed the protective effects of glucocorticoids against heatstroke-induced arterial hypotension and ischaemic neuronal damage. Heatstroke was induced by exposing the animals to an ambient temperature of 42 C. The time at which both the mean arterial pressure (MAP) and local cerebral blood flow (CBF) in the striatum decreased from their peak levels was taken as the onset of heatstroke. Control rats were exposed to a temperature of 24 C. The values of MAP and CBF after heatstroke onset were all significantly lower than those in control rats. However, the neuronal damage score in the striatum and serum levels of interleukin-1beta (IL-1beta) were greater. Systemic pretreatment or treatment with an exogenous glucocorticoid, dexamethasone (4 mg or 6 mg kg-1, i.v.), reduced the heatstroke-induced arterial hypotension, serum IL-1beta levels, cerebral ischaemia and neuronal damage, and resulted in prolongation of the time to death (TTD; the interval between the onset of heat stress and cardiac arrest). Following bilateral adrenalectomy, MAP, CBF and TTD values were found to be significantly lower in the adrenalectomized (ADX) rats than in the sham-ADX rats after heat exposure. These changes were attenuated by dexamethasone. The data support the argument that glucocorticoids reduce the plasma IL-1beta concentration and may provide the neuroprotective effects observed in rat heatstroke.
Adrenalectomy↗
Increased apoptosis of peripheral blood T cells following allogeneic hematopoietic cell transplantation.
Lymphopenia and immune deficiency are significant problems following allogeneic hematopoietic cell transplantation (HCT). It is largely assumed that delayed immune reconstruction is due to a profound decrease in thymus-dependent lymphopoiesis, especially in older patients, but apoptosis is also known to play a significant role in lymphocyte homeostasis. Peripheral T cells from patients who received HCT were studied for evidence of increased cell death. Spontaneous apoptosis was measured in CD3(+) T cells following a 24-hour incubation using 7-amino-actinomycin D in conjunction with the dual staining of cell surface antigens. Apoptosis was significantly greater among CD3(+) T cells taken from patients 19-23 days after transplantation (30.4% +/- 12.5%, P <.05), and 1 year after transplantation (9.7% +/- 2.8%, P <.05) compared with healthy controls (4.0% +/- 1.5%). Increased apoptosis occurred preferentially in HLA (human leukocyte antigen)-DR positive cells and in both CD3(+)/CD4(+) and CD3(+)/CD8(+) T-cell subsets, while CD56(+)/CD3(-) natural killer cells were relatively resistant to apoptosis. The extent of CD4(+) T-cell apoptosis was greater in patients with grade II-IV acute graft-versus-host disease (GVHD) (33. 9% +/- 11.3%) compared with grade 0-I GVHD (14.6 +/- 6.5%, P <.05). T-cell apoptosis was also greater in patients who received transplantations from HLA-mismatched donors (39.5% +/- 10.4%, P <. 05) or HLA-matched unrelated donors (32.1% +/- 11.4%, P <.05) compared with patients who received transplantations from HLA-identical siblings (19.6% +/- 6.7%). The intensity of apoptosis among CD4(+) T cells was significantly correlated with a lower CD4(+) T-cell count. Together, these observations suggest that activation of T cells in vivo, presumably by alloantigens, predisposes the cells to spontaneous apoptosis, and this phenomenon is associated with lymphopenia. Activation-induced T-cell apoptosis may contribute to delayed immune reconstitution following HCT. (Blood. 2000;95:3832-3839)
Acute Disease↗
Involvement of tyrosine kinase in the pyrogenic fever exerted by NOS pathways in organum vasculosum laminae terminalis.
Nitric oxide synthase (NOS) is an enzyme which has a distinct cytokine-inducible isoform (iNOS). Many cytokine receptors have an intracellular tyrosine kinase domain. Here we have used two tyrosine kinase inhibitors (genistein and lavendustin A) to investigate the potential role of tyrosine kinase activation in the induction on both iNOS and fever caused by lipopolysaccharide (LPS) in rabbits. Direct administration of LPS into the organum vasculosum laminae terminalis (OVLT) increased iNOS expression. These increases paralleled the increase in deep body temperature in unanesthetized rabbits. Pretreatment with genistein or lavendustin A not only reduced the fever but also attenuated the iNOS expression in the OVLT following an intra-OVLT dose of LPS. These results suggest that tyrosine phosphorylation is part of the signal transduction mechanism that mediates the induction of both iNOS and fever elicited by LPS in the OVLT of rabbit brain.
Animals↗
Epstein-Barr virus-associated gastric carcinomas: relation to H. pylori infection and genetic alterations.
BACKGROUND & AIMS: The association of Epstein-Barr virus (EBV) and gastric carcinomas (GCs) has been shown to vary among different populations and certain histological subtypes. Few studies have addressed the status of Helicobacter pylori infection and genetic alterations in these EBV-positive or -negative GCs. METHODS: Eleven gastric lymphoepithelioma-like carcinomas (LELCs) and 139 cases of common non-LELCs were evaluated for the presence of EBV DNA using polymerase chain reaction (PCR) and RNA in situ hybridization. H. pylori infection was determined by anti-H. pylori immunoglobulin G in preoperative sera. Immunostaining for p53, c-erbB-2, and E-cadherin was performed. Microsatellite instability was analyzed by PCR using 10 primers. RESULTS: EBV was detected in 11 (100%) LELCs and in 19 (13.7%) of 139 common GCs. Compared with EBV-negative GCs, gastric LELCs tended to have a relatively higher frequency of proximal location, diffuse histological subtype, p53 overexpression, and reduced E-cadherin expression but a lower frequency of lymph node metastasis, previous H. pylori infection, and c-erbB-2 overexpression. In contrast, no significant difference of clinicopathologic and genetic profiles was observed between EBV-positive non-LELC GCs and EBV-negative GCs. No correlation of microsatellite instability was found among these 3 subsets of GCs. CONCLUSIONS: Dissecting clinicopathologic characteristics and infection status of EBV and H. pylori provide additional evidence of etiological and genetic heterogeneity for GC. Distinct clinicopathologic and genetic pathways exist in gastric LELCs, in which EBV may play a more important role than H. pylori infection.
Adenocarcinoma↗
Cutaneous gene therapy. Principles and prospects.
As investigators continue to close the gap between basic research and clinical science, gene therapy is becoming of increasing interest to the dermatologist. Most notably, recent advances in gene-based cancer therapy, DNA vaccination, and molecular pharmacology have opened new avenues for investigation beyond those of the traditional gene replacement applications. Different gene delivery systems are currently being tested, each with specific advantages and disadvantages. This article summarizes some of the principles of gene therapy and its applications to cutaneous diseases.
Genetic Therapy↗
Effects of parenteral infusion with fish-oil or safflower-oil emulsion on hepatic lipids, plasma amino acids, and inflammatory mediators in septic rats.
This study was designed to investigate the effects of preinfusion with total parenteral nutrition (TPN) using fish-oil (FO) versus safflower-oil (SO) emulsion as fat sources on hepatic lipids, plasma amino-acid profiles, and inflammatory-related mediators in septic rats. Normal rats, with internal jugular catheters, were assigned to two different groups and received TPN. TPN provided 300 kcal. kg(-1). d(-1), with 40% of the non-protein energy as fat. All TPN solutions were isonitrogenous and identical in nutrient composition except for the fat emulsion, which was made of SO or FO. After receiving TPN for 6 d, each group of rats was further divided into control and sepsis subgroups. Sepsis was induced by cecal ligation and puncture; control rats received sham operation. All rats were classified into four groups as follows: FO control group (FOC; n = 7), FO sepsis group (FOS; n = 8), SO control group (SOC; n = 8), and SO sepsis group (SOS; n = 9). The results of the study demonstrated that plasma concentrations of triacylglycerol and non-esterified fatty acids did not differ between the FO and SO groups, regardless of whether the animals were septic. SOS had significantly higher total lipids and cholesterol content in the liver than did the SOC group. The FOS group, however, showed no difference from the FOC group. Plasma leucine and isoleucine levels were significantly lower in the SOS group than in the SOC group, whereas no difference in these two amino acids was observed between the FOC and FOS groups. Plasma arginine levels were significantly lower in both septic groups than in the groups without sepsis when either FO or SO was infused. Plasma glutamine levels, however, did not differ across groups. No differences in interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, or leukotriene B(4) concentrations in peritoneal lavage fluid were observed between the two septic groups. These results suggest that catabolic reaction in septic rats preinfused with FO is not as obvious as those preinfused with SO. Compared with SO emulsion, TPN with FO emulsion prevents liver fat accumulation associated with sepsis. However, parenterally administered FO had no beneficial effect in lowering cytokines and LTB(4) levels in peritoneal lavage fluid in septic rats induced by cecal ligation and puncture.
Amino Acids↗
Molecular modeling of the minor histocompatibility antigen HA-1 peptides binding to HLA-A alleles.
Mismatch of the minor histocompatibility antigen HA-1 has been shown to correlate with graft-versus-host disease in HLA-matched sibling marrow transplants. The HA-1H peptide (VLHDDLLEA) that generates this response is known to be presented by HLA-A*0201. In order to understand the interaction of HA-1 peptides with other HLA-A alleles, we have used the LOOK interface to construct molecular models of both HA-1H peptide (VLHDDLLEA) and HA-1R peptide (VLRDDLLEA) binding with 103 HLA-A alleles. The results show that in addition to A*0201, 21/103 other HLA-A alleles should be able to bind HA-1H peptide but not HA-1R peptide. Based on the modeled predictions, HLA alleles can be categorised into 4 groups with respect to their interaction with HA-1 peptides: Group 1 - bind HA-1H peptide but not HA-1R peptide; Group 2 - bind HA-1R peptide but not HA-1H peptide; Group 3 - bind both HA-1H and HA-1R peptides; Group 4 - bind neither peptide. These predicted binding patterns of HA-1 peptides will be useful as an aid for defining a wider pool of HLA-A alleles in which HA-1 disparities among donor-recipient pairs can be investigated.
Alleles↗
Expression of Tie-2, angiopoietin-1, angiopoietin-2, ephrinB2 and EphB4 in pyogenic granuloma of human gingiva implicates their roles in inflammatory angiogenesis.
Tie-2, angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), ephrin-B2 and Eph-B4 are all important vascular morphogenesis factors which exhibit their functions in angiogenesis and blood vessel remodeling in embryonic stage. However, their roles in post-natal inflammatory angiogenesis are still unclear. Pyogenic granuloma is a benign inflammatory lesion that mostly occurs on the gingiva of females with high levels of steroid hormones. Prominent capillary growth in hyperplastic granulation tissue is characteristic histopathologically in pyogenic granuloma. The purpose of this study was to detect and compare the expressions of Tie-2, Ang-1, Ang-2, ephrin-B2 and Eph-B4 among pyogenic granuloma on human gingiva, gingiva diagnosed with periodontitis and healthy gingiva by immunohistochemistry. The immunostaining revealed that all of the endothelial cells and some mesenchymal cells expressed Tie-2. The cells which expressed Ang-1 and Ang-2 were mainly macrophage- or monocyte-like mesenchymal cells and smooth muscle cells surrounding blood vessels. The expression of ephrin-B2 and Eph-B4 was not exclusively limited to the endothelial cells of arteries and veins, respectively, as in mice embryo. Eph-B4 was expressed in the endothelial cells of newly budding capillaries and venules while ephrin-B2 was expressed in macrophage-like mesenchymal cells. Some of the ephrin-B2 positive cells were in direct contact with endothelial cells. The statistical analysis demonstrated that all of the five factors were upregulated in pyogenic granuloma compared to healthy gingiva. In conclusion, the 5 polypeptides mentioned above may play important roles in the process of adult inflammatory neovascularization, especially in pyogenic granuloma. It is highly plausible that most of the new capillaries in inflammatory angiogenesis originated from venules instead of arterioles.
Adult↗
The gene gun: current applications in cutaneous gene therapy.
Explore the source record for details and available documents.
Animals↗
Staphylococcal enterotoxin A acts through nitric oxide synthase mechanisms in human peripheral blood mononuclear cells to stimulate synthesis of pyrogenic cytokines.
The pyrogenic response to supernatant fluids obtained from human peripheral blood mononuclear cells (PBMC) stimulated with staphylococcal enterotoxin A (SEA) was characteristic of a response to an endogenous pyrogen in that it was brief and monophasic and was destroyed by heating supernatant fluids at 70 degrees C for 30 min. The febrile responses were in parallel with the levels of interleukin-1 (IL-1), tumor necrosis factor (TNF), interferon-gamma (IFN-gamma), IL-2, and IL-6 in supernatant fluids obtained from PBMC treated with SEA. Both the pyrogenicity and the levels of IL-1, TNF, IFN-gamma, IL-2, and IL-6 in supernatant fluids started to rise at 6 to 18 h and reached their peak levels at 24 to 96 h after SEA incubation. Both the fever and the increased levels of IL-1, TNF, IFN-gamma, IL-2, and IL-6 in supernatant fluids obtained from the SEA-stimulated PBMC were decreased by incubating SEA-PBMC with anisomycin (a protein synthesis inhibitor), aminoguanidine (an inhibitor of inducible nitric oxide synthase [NOS]), or dexamethasone (an inhibitor of NOS). The febrile response to supernatant fluids obtained from the SEA-stimulated PBMC was attenuated by adding either anti-IL-1beta, anti-TNF-alpha, or anti-IFN-gamma monoclonal antibody (MAb) to supernatant fluids. The antipyretic effects exerted by anti-IL-1beta MAb were greater than those exerted by anti-TNF-alpha or anti-IFN-gamma MAb. The data suggest that SEA acts through the NOS mechanisms in PBMC to stimulate synthesis of pyrogenic cytokines (in particular, the IL-1beta).
Animals↗