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Biomedical subjects

K L Erickson

Publications and source records attributed to K L Erickson.

At least 37 records · Page 2Linked to original sources
PubMed1999

Docosahexaenoic acid ingestion inhibits natural killer cell activity and production of inflammatory mediators in young healthy men.

The purpose of this study was to examine the effects of feeding docosahexaenoic acid (DHA) as triacylglycerol on the fatty acid composition, eicosanoid production, and select activities of human peripheral blood mononuclear cells (PBMNC). A 120-d study with 11 healthy men was conducted at the Metabolic Research Unit of Western Human Nutrition Reach Center. Four subjects (control group) were fed the stabilization diet throughout the study; the remaining seven subjects were fed the basal diet for the first 30 d, followed by 6 g DHA/d for the next 90 d. DHA replaced an equivalent amount of linoleic acid; the two diets were comparable in their total fat and all other nutrients. Both diets were supplemented with 20 mg D alpha-tocopherol acetate per day. PBMNC fatty acid composition and eicosanoid production were examined on day 30 and 113; immune cell functions were tested on day 22, 30, 78, 85, 106, and 113. DHA feeding increased its concentration from 2.3 to 7.4 wt% in the PBMNC total lipids, and decreased arachidonic acid concentration from 19.8 to 10.7 wt%. It also lowered prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) production, in response to lipopolysaccharide, by 60-75%. Natural killer cell activity and in vitro secretion of interleukin-1beta and tumor necrosis factor alpha were significantly reduced by DHA feeding. These parameters remained unchanged in the subjects fed the control diet. B-cell functions as reported here and T-cell functions that we reported previously were not altered by DHA feeding. Our results show that inhibitory effects of DHA on immune cell functions varied with the cell type, and that the inhibitory effects are not mediated through increased production of PGE2 and LTB4.

Administration, Oral↗
PubMed1999

Effects of tumor necrosis factor alpha on leptin secretion and gene expression: relationship to changes of glucose metabolism in isolated rat adipocytes.

OBJECTIVE: Our objective was to determine the effects of prolonged exposure to tumor necrosis factor-alpha (TNF-alpha) on leptin secretion from and leptin (OB) gene expression in isolated adipocytes. Because glucose uptake and the metabolism of glucose beyond lactate are important determinants of leptin production in adipocytes, we examined the effects of TNF-alpha on glucose uptake and lactate production and their relationship to leptin secretion. DESIGN AND METHODS: Isolated rat adipocytes were anchored in a defined matrix of basement membrane components and cultured with media containing 5 mM glucose, 0.16 nM insulin and several concentrations of TNF-alpha. Leptin secretion, steady-state levels of leptin mRNA levels, glucose uptake, and lactate production were assessed over 96 h. RESULTS: TNF-alpha at concentrations of 0.024, 0.24, 2.4 and 24 ng/ml did not affect leptin secretion over 24 h. TNF-alpha at concentrations of 0.24 to 24 ng/ml significantly inhibited leptin secretion over 96 h by 19-60%. TNF-alpha at concentrations of 0.024 to 24 ng/ml significantly decreased steady-state levels of leptin mRNA after 96 h by 32-95%. In addition, TNF-alpha at concentrations of 2.4 and 24 ng/ml significantly increased glucose uptake and lactate production over 96 h by 30-57%. TNF-alpha at a concentration of 0.024 ng/ml did not affect leptin secretion, glucose uptake or lactate production. Overall, for the TNF-alpha concentrations tested, leptin secretion was inversely related to the percent of glucose carbon released as lactate; however, TNF-alpha did not induce a proportional increase of lactate production from glucose. CONCLUSION: Short-term (24 h) exposure of isolated adipocytes to TNF-alpha does not affect leptin secretion. Prolonged exposure to TNF-alpha produces a concentration-dependent inhibition of leptin secretion and gene expression. This suggests that the acute effect of TNF-alpha to increase circulating leptin levels in vivo may be indirect. TNF-alpha at higher concentrations increases glucose uptake, but does not increase the conversion of glucose to lactate. Therefore, TNF-alpha appears to induce a dissociation between adipocyte glucose metabolism and leptin production.

Adipocytes↗
PubMed1999

Tumor necrosis factor depresses myocardial contractility in endotoxemic swine.

BACKGROUND: Depression of myocardial contractility occurs in septic shock. METHODS: Fourteen pigs were instrumented to measure cardiopulmonary dynamics after a challenge of Escherichia coli endotoxin (lipopolysaccharide endotoxin, LPS). A volumetric Swan-Ganz catheter was placed via the jugular vein, and a carotid arterial line was placed into the aortic root. Eight pigs received LPS alone and six pigs received tumor necrosis factor monoclonal antibody (TNF MAb) 15 minutes before the administration of LPS. Pulmonary artery and aortic root blood were sampled for amounts of TNF. Ninety minutes after LPS administration, thoracotomy was performed to biopsy the right and left ventricles for TNF levels. Contractility was determined from the end systolic pressure-volume relationships of pressure-volume diagrams. RESULTS: Right ventricular end diastolic volume index nearly doubled and myocardial contractility decreased by 40% from baseline in the pigs receiving only LPS. Pigs that received TNF MAb had no change in myocardial contractility or right ventricular end diastolic volume index from baseline. There was a higher level of TNF in the aortic sample than in the pulmonary samples at 60 minutes. Right ventricular tissue TNF levels were significantly higher in the LPS-alone group. There was no such difference in left ventricular tissue. CONCLUSION: The left and right ventricles have different susceptibilities to TNF MAb. TNF may decrease myocardial contractility in sepsis. Blockade of TNF with TNF MAb reverses the depression of myocardial contractility and the right ventricular dilatation associated with septic shock.

Animals↗
PubMed1998

Inductive electron-withdrawal from ammonium ion headgroups of cationic lipids and the influence on DNA transfection.

We have prepared a panel of lipidic ammonium tetrafluoroborate salts that contain trifluoromethyl, trichloromethyl, and methyl groups attached to the headgroup. 19F-NMR analyses of the cationic lipid panel revealed that the differences in electron-withdrawal from the ammonium ion headgroup accounted for differences in ion-pairing. Exchange of the tetrafluoroborate counterion by complexation to DNA-phosphate of a reporter gene enabled us to probe the influence of inductive electron-withdrawal in cationic lipid-mediated DNA transfection. We tested the lipid panel for transfection activity in two cell lines. The results indicate that the inductive effects of electron-withdrawing functionality diminish transfection activity in modest (2-4-fold) increments. The present study suggests that the mechanism whereby poly(alcohol)- or poly(ether)-substituted headgroups improve DNA transfection is not based on electronic activation of the ammonium ion.

Adenocarcinoma↗
PubMed1998

Alteration of murine mammary tumorigenesis by dietary enrichment with n-3 fatty acids in fish oil.

We and others have previously shown that dietary fat can alter the growth and metastasis of rodent mammary tumors. Few transplantable tumor models have been used to study the effects of dietary n-6 versus n-3 fatty acids on mammary tumorigenesis. Here we study the effects of fish oil and safflower oil on the growth and metastasis of an animal model that in several ways parallels the human disease. Tumor latency, growth and metastasis were studied in mice fed diets that contained either 10 or 20% total fat which was varied in the type of fat with either menhaden fish oil (FO), safflower oil (SO) or a 50/50 mixture of the two. Tumor latency was significantly longer and tumor growth was significantly slower in mice fed the 20% FO diet. When spontaneous metastasis was assessed, mice fed diets containing FO had significantly decreased numbers of pulmonary nodules and total metastatic load. Likewise, mice fed FO diets had a lower level of implantation and survival of pulmonary metastases. Thus, in our animal model, diets containing n-3 fatty acids in fish oil significantly decrease primary breast tumor growth and its metastasis.

Adenocarcinoma↗
PubMed1998

Modulation of select immune responses by dietary capsaicin.

Capsaicin (CAP) is the spicy principle of hot peppers that has been used as a food additive, preservative, and medicine. In this study, we investigated the effect of dietary CAP on immune status and selected immune responses. BALB/c mice were divided into 5 groups and fed diets with either 0, 5, 20, 50 or 100 ppm CAP for 3 weeks. The parameters measured with lymphocytes included mitogen-induced proliferation, plaque-forming cell number, and total serum immunoglobulin levels. In spleen cells of mice fed 20 ppm CAP there was a greater T-cell mitogen induced, lymphocyte proliferative response. In addition, the number of antibody-producing B cells and serum IgG and IgM levels increased in mice fed 20 ppm CAP as compared to the control with no CAP. The effect of dietary CAP on macrophage activity was assessed by phagocytosis and tumor necrosis factor-alpha (TNF alpha) production. Dietary CAP had no effect on phagocytic activity by peritoneal macrophages, but the levels of secreted TNF alpha increased in the groups fed 20 ppm CAP compared to the control. These results suggest that dietary CAP may differentially enhance immune status as well as select immune functions. That is in contrast with previous studies that show immunosuppression observed after CAP injection.

Animals↗
PubMed1997

Factors altering ribozyme-mediated cleavage of tumor necrosis factor-alpha mRNA in vitro.

Hammerhead ribozymes are capable of cleaving RNA in a sequence specific manner in vitro. However, the complex environment of the cell differs dramatically from the conditions in vitro. Therefore, we explored cleavage of full-length target RNA with two ribozymes targeted against the murine tumor necrosis factor-alpha (TNF-alpha) mRNA. These ribozymes cleaved TNF-alpha mRNA within a pool of total cellular RNA in vitro, but less efficiently than previously reported for similar ribozymes. Although there may be several factors that could affect ribozyme activity, two of these factors were tested. The first factor was whether non-target polynucleotides inhibited ribozyme-mediated cleavage. Total cellular RNA and to a lesser degree DNA inhibited ribozyme activity. This inhibition was a combination of competitive and non-competitive inhibition. Non-target RNA with minimal complementarity to the ribozyme or target showed no effect on cleavage rates. The second factor was whether denaturing conditions improved ribozyme cleavage efficiency. Hammerhead ribozymes with 24 complementary bases had increased cleavage efficiency in formamide. Thus, the ribozymes may have had too long of an antisense flanking sequence which hybridized with the target RNA and resulted in a high melting temperature. These studies demonstrate that ribozyme cleavage was influenced by the amount of non-target polynucleotide and the strength of the ribozyme-substrate interaction.

Base Sequence↗
PubMed1997

Alteration of platelet-activating factor-induced signal transduction in macrophages by n-3 fatty acids.

Diets rich in polyunsaturated n-3 fatty acids can alter various macrophage functions. One possible mechanism by which this occurs is through modulation of the physicochemical properties of the cell membrane and the signal transduction pathways associated with macrophage activation. In this study, we investigated how n-3 fatty acids altered the signaling pathway of the lipid-based mediator platelet-activating factor (PAF). Macrophages from mice fed a diet containing n-3 fatty acids showed a greater increase in PAF-induced intracellular Ca2+ mobilization than macrophages from mice fed an n-6 fatty acid-rich diet. Macrophages treated in vitro with the n-3 fatty acids docosahexaenoic and eicosapentaenoic also showed higher intracellular Ca2+ mobilization than untreated or n-6 fatty acid-treated macrophages. Scatchard analysis of PAF binding showed the presence of one type of PAF receptor; their number and affinities were not altered by dietary fat. Mastoparan, which can activate G-protein-linked phosphoinositide (PI)-signaling pathway through the activation of G proteins, stimulated a higher Ca2+ mobilization in macrophages from mice fed n-3 compared to n-6 fatty acids. In addition, the response of macrophages from n-3-fed mice to PAF was less sensitive to phospholipase C inhibition than that of macrophages from those fed n-6 diets. The activity of phospholipase C in macrophages from mice fed n-3 diets was significantly higher than that of macrophages from mice fed diets containing n-6 fatty acids. Collectively, these results showed that n-3 fatty acids can enhance the PAF-signaling pathway in macrophages by increasing the activation potential of phospholipase C, without affecting PAF receptor number and affinity.

Animals↗
PubMed1997

Induction and modulation of macrophage Ia antigen expression by platelet-activating factor.

Expression of major histocompatibility complex class II molecules, Ia, can be significantly augmented by interferon-gamma (IFN-gamma) in macrophages. In this study we demonstrate that platelet-activating factor (PAF) was also a potent inducer of Ia antigen expression on macrophages. PAF-induced Ia expression was both time- and dose-dependent. Maximal Ia expression was induced with 25 nM PAF after 3-h exposure to PAF. Ia expression in macrophages stimulated with PAF for 24 h was not significantly greater than unstimulated macrophages. Treatment of macrophages with IFN-gamma and PAF did not affect either the kinetics or concentration required for maximal Ia expression induced by either IFN-gamma or PAF. PAF-induced Ia expression was inhibited by the specific PAF receptor antagonists, WEB 2086, Ro 24-0238, and Ro 24-4637, indicating a receptor-mediated event. Like IFN-gamma-induced Ia expression, PAF activity was inhibited by prostaglandin E2 (PGE2). However, that expression was only inhibited after 24 h when macrophages were treated with the PGE2 synthesis inhibitors, flurbiprofen and indomethacin. These findings demonstrate that PAF, along with its role as a potent proinflammatory mediator, was also capable of inducing Ia expression on macrophages through the PAF receptor and that expression was altered by PGE2.

Animals↗
PubMed1997

Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice.

We constructed two megabase-sized YACs containing large contiguous fragments of the human heavy and kappa (kappa) light chain immunoglobulin (Ig) loci in nearly germline configuration, including approximately 66 VH and 32 V kappa genes. We introduced these YACs into Ig-inactivated mice and observed human antibody production which closely resembled that seen in humans in all respects, including gene rearrangement, assembly, and repertoire. Diverse Ig gene usage together with somatic hypermutation enables the mice to generate high affinity fully human antibodies to multiple antigens, including human proteins. Our results underscore the importance of the large Ig fragments with multiple V genes for restoration of a normal humoral immune response. These mice are likely to be a valuable tool for the generation of therapeutic antibodies.

Amino Acid Sequence↗
PubMed1997

Enhancement of B-cell translocation gene-1 expression by prostaglandin E2 in macrophages and the relationship to proliferation.

Although prostaglandin (PG) E2 is known to suppress various macrophage functions, the molecular mechanisms by which that occurs are largely unknown. To understand better those mechanisms, differential screening of a cDNA library from PGE2-treated macrophages was performed. Subsequently, the DNA sequence of a differentially expressed cDNA clone was determined and the cDNA was identified as B-cell translocation gene-1 (BTG1), a recently cloned antiproliferative gene. A two-to threefold increase in macrophage BTG1 expression was observed after PGE2 treatment. PGE1 and platelet-activating factor, but not leukotrienes B4, and C4, or lipopolysaccharide, also enhanced BTG1 expression. Furthermore, this effect ws mimicked by dibutyryl cAMP which indicated the involvement of elevated cAMP in the PGE2-mediated enhancement of BTG1. Moreover, there was an inverse correlation between BTG1 mRNA expression and macrophage proliferation; however, BTG1 alteration was not associated with macrophage tumoricidal activation. Thus, BTG1 may play a role in PGE2-mediated inhibition of macrophage proliferation and not activation.

Animals↗
PubMed1996

Alteration of macrophage responsiveness to platelet-activating factor by interferon-gamma and lipopolysaccharide.

Platelet-activating factor (PAF) can modulate several macrophage responses associated with tumoricidal and inflammatory activity. To determine how macrophage responsiveness to PAF may be altered by interferon-gamma (IFN-gamma) or lipopolysaccharide (LPS), we studied PAF receptor-associated activities. Pretreatment of murine peritoneal macrophages with either LPS or IFN-gamma suppressed macrophage responsiveness to both PAF-induced calcium mobilization and superoxide anion (O2-) production. This suppression of macrophage responsiveness to PAF was maximal when 25 U/ml IFN-gamma or 100 ng/ml LPS was initially added for 6 hr. Macrophages pretreated with LPS or IFN-gamma remained refractory to PAF-induced rise in intracellular calcium for 4 to 24 hr. Macrophages preincubated with 25 U/ml IFN-gamma remained refractory to PAF-induced calcium mobilization for up to 4 hr. LPS and IFN-gamma treatment also decreased PAF-induced, calcium-dependent O2- production. When added together, IFN-gamma increased the suppression of PAF-induced intracellular calcium mobilization and inhibited O2- production mediated by LPS. To assess whether suppression was mediated through altered PAF receptors, binding affinities were determined; two binding affinities were demonstrated. Initial incubation of macrophages with LPS or IFN-gamma added alone or together decreased the number of cell surface PAF receptors and their binding affinity. These studies demonstrated that pretreatment with IFN-gamma and LPS can suppress select PAF-induced macrophage functions. Downregulation of PAF receptor activity may represent a means by which macrophages regulate the capacity and magnitude of some PAF-induced responses.

Animals↗
PubMed1996

Tyrosine kinase but not phospholipid/Ca2+ signaling pathway is involved in interferon-gamma stimulation of Ia expression in macrophages.

The specific signal transduction pathway(s) involved in the induction of the expression of the MHC class II molecule, Ia, on macrophages by interferon-gamma (IFN-gamma) is unclear. In this paper, we assessed the role of several signal transduction pathways including calcium mobilization, phospholipase C, protein kinase C and cyclic nucleotide-dependent protein kinase, and the tyrosine kinase pathways. IFN-gamma was unable to mobilize intracellular calcium, unlike platelet-activating factor, which stimulated a threefold increase in cytosolic Ca2+ concentration in macrophages. Inhibition of the phospholipase C pathway by U73122 or ET-180CH3 and of phosphatidic acid phosphohydrolase by propranolol did not suppress IFN-gamma-induced Ia expression. In addition, inhibition of protein kinase C by calphostin C or cyclic nucleotide-dependent protein kinase by HA1004 did not suppress Ia expression. However, IFN-gamma-induced Ia expression was significantly suppressed when the tyrosine kinase pathway was inhibited with herbimycin A and genestein. In addition, those two inhibitors suppressed tyrosine phosphorylation of several proteins in macrophages that may or may not be involved in the induction of Ia expression. Thus, IFN-gamma used only the tyrosine kinase signaling pathway, but not the phospholipid/Ca2+ signaling pathways, to induce Ia expression in macrophages.

Animals↗
PubMed1996

Toxicity of cationic lipid-ribozyme complexes in human prostate tumor cells can mimic ribozyme activity.

Prostate tumor cell lines have been shown to both produce interleukin-6 (IL-6) and express the IL-6 receptor, suggesting a potential autocrine growth regulatory role for IL-6. We explored the role of IL-6 in the proliferation of the human prostatic carcinoma cell line, DU145, using ribozymes to inhibit IL-6 expression. Hammerhead-type ribozymes targeted against IL-6 mRNA sequences were prepared, and in vitro analyses were used to demonstrate that these molecules catalyzed the cleavage of IL-6 mRNA poly- nucleotide fragments. To test in situ activity, these ribozymes were transfected into DU145 cells using cationic transfection lipids, cytofectins. Treatment of cultured cells with ribozyme/cationic lipid complexes resulted in a reduction of IL-6 protein levels in the supernatant and reduced numbers of DU145 cells 48 h after treatment. However, similar results were also seen following treatment with control RNA/lipid complexes. This reduction in IL-6 levels and cell numbers was a function of the RNA/lipid complexes and was not seen with either lipid or RNA alone. Therefore, the reductions in IL-6 levels and cell numbers observed were not due to ribozyme-mediated cleavage of IL-6 mRNA, but rather reflected a dose-dependent, nonspecific toxic effect of the treatment with ribozyme/cytofectin complexes. This effect can resemble functional ribozyme activity, complicating analysis of the activity of synthetic ribozymes after transfection into cultured cells.

Base Sequence↗