Biomedical subjects

K L Erickson

Publications and source records attributed to K L Erickson.

At least 55 records · Page 3Linked to original sources

PubMed1996

Dietary fish oil modulation of macrophage tumoricidal activity.

Recent studies have shown that macrophages and their functions can be altered by dietary fat. Specifically, diets that are rich in n-3 fatty acids such as fish oils can have significant effects on macrophage cytolytic capacity and the production of select cytokines. The purpose of these studies was to characterize how dietary fish oils altered macrophage tumoricidal activity and the production of tumor necrosis factor-alpha (TNF-alpha). Dietary menhaden fish oil (MFO) significantly decreased the ability of activated macrophages to kill tumor targets compared with macrophages from mice fed safflower oil (SAF), which is high in n-6 fatty acids. Those macrophages from mice fed MFO were hyporesponsive to interferon-gamma. In addition, macrophages from mice fed MFO produced more TNF-alpha after 24 h activation with lipopolysaccharide compared with macrophages from mice fed SAF. That difference in TNF-alpha production was associated with a differential production of and response to prostaglandin E2. Although there are several possible mechanisms by which dietary fat may alter macrophage function and cytokine production, we have investigated signal transduction. Macrophages from MFO-fed mice had a greater increase in intracellular calcium mobilization after treatment with platelet-activating factor (PAF) than macrophages from mice fed SAF. Those differences may be related to an alteration in the PAF signalling pathway by increasing phospholipase C activity. Thus, dietary n-3 fatty acids may significantly alter macrophage tumoricidal activation and TNF-alpha production through the modulation of PGE2 production and signal transduction.

Animals↗

PubMed1996

Differential regulation of tumour necrosis factor-alpha mRNA degradation in macrophages by interleukin-4 and interferon-gamma.

Interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) have been reported previously to mediate similar as well as antagonistic effects on murine macrophage functions. One effect common to both is the enhancement of tumour necrosis factor-alpha (TNF-alpha) secretion in macrophages. To assess further the effects of these two lymphokines on macrophage TNF-alpha production, we investigated the role of these lymphokines in the induction and stability of TNF-alpha messages along with interleukin-1 (IL-1) as a comparison. IFN-gamma and IL-4 increased lipopolysaccharide (LPS)-induced TNF-alpha, IL-1 steady-state message levels. In contrast to IL-1 messages, whose degradation was not significantly affected by either lymphokine, the stability of TNF-alpha messages differed after IFN-gamma and IL-4 treatment. Although IL-4 treatment increased the TNF-alpha transcription rate, an increase in the degradation rate of TNF-alpha mRNA in the IL-4-treated cells resulted in a lower level of steady-state mRNA than in the IFN-gamma-treated cells. Additionally, a 18,000 MW cytoplasmic factor was found to have specific binding activity to the AU-rich sequences of the TNF-alpha message in peritoneal macrophages. Although the binding activity of this factor was not affected by either IFN-gamma or IL-4, the binding of the factor to AU-rich sequences appeared to be important in the rapid degradation of TNF-alpha messages. Thus IFN-gamma and IL-4 may differentially affect the post-transcriptional control of TNF-alpha gene expression. And this lymphokine-mediated post-transcriptional control of the TNF-alpha gene does not appear to involve the alteration of binding activity of the 18,000 MW AU-rich sequence binding factor.

Animals↗

PubMed1996

Dietary myristic acid alters acylated proteins in activated murine macrophages.

After stimulation with select activating agents such as lipopolysaccharide (LPS) or recombinant interferon-gamma (rIFNgamma), several macrophage proteins may be induced, acylated with myristic acid, or both. Our goal in this study was to determine whether altering the levels of myristic acid in the diet would modulate the levels of a specific acylated macrophage protein, MacMARCKS (myristoylated, alanine-rich C kinase substrate), because that fatty acid can be found in substantial quantities in some foods. Thioglycollate-elicited peritoneal macrophages from groups of mice fed diets with various levels of myristic acid (from 0.2 to 99 g/100 g fatty acids) were treated with LPS, phorbol myristate acetate (PMA), or rIFNgamma plus LPS, which are well-established macrophage activating agents. Levels of MacMARCKS were measured by enzyme-linked immunosorbent assay using a rabbit anti-mouse polyclonal antibody against the first 10 amino acids of murine MacMARCKS. A 42-kDa protein with the same molecular weight as MacMARCKS was identified in macrophage lysates by Western analysis using the antibody. Lipopolysaccharide- and PMA-activated macrophages from mice fed the trimyristin diet had significantly greater levels of MacMARCKS than LPS- and PMA-activated macrophages of mice fed the safflower oil-containing diet. The levels of MacMARCKS were also greater in lysates of LPS plus rIFNgamma-stimulated macrophages from mice fed the trimyristin diet and mice fed a diet containing a moderate level of myristic acid (12 g/100 g fatty acids) compared with the lysates of macrophages from mice fed the safflower oil diet. These results indicate that altering the level of myristic acid in the diet may alter the production of specific proteins that may be involved in macrophage activation.

Acylation↗

PubMed1995

T cell receptor-mediated Ca2+ signaling: release and influx are independent events linked to different Ca2+ entry pathways in the plasma membrane.

In this study, we showed that cross-linking CD3 molecules on the T cell surface resulted in Ca2+ release from the intracellular stores followed by a sustained Ca2+ influx. Inhibition of release with TMB-8 did not block the influx. However, inhibition of phospholipase C activity suppressed both Ca2+ release and influx. Once activated, the influx pathway remained open in the absence of further hydrolysis of PIP2. Thapsigargin, a microsomal Ca(2+)-ATPase inhibitor, stimulated Ca2+ entry into the cells by a mechanism other than emptying Ca2+ stores. In addition, Ca2+ entry into the Ca(2+)-depleted cells was stimulated by low basal level of cytosolic Ca2+, not by the emptying of intracellular Ca2+ stores. Both the Ca2+ release and influx were dependent on high and low concentrations of extracellular Ca2+. At low concentrations, Mn2+ entered the cell through the Ca2+ influx pathway and quenched the sustained phase of fluorescence; whereas, at higher Mn2+ concentration both the transient and the sustained phases of fluorescence were quenched. Moreover, Ca2+ release was inhibited by low concentrations of Ni2+, La3+, and EGTA, while Ca2+ influx was inhibited by high concentrations. Thus, in T cells Ca2+ influx occurs independently of IP3-dependent Ca2+ release. However, some other PIP2 hydrolysis-dependent event was involved in prolonged activation of Ca2+ influx. Extracellular Ca2+ influenced Ca2+ release and influx through the action of two plasma membrane Ca2+ entry pathways with different pharmacological and biochemical properties.

Animals↗

PubMed1995

The induction and augmentation of macrophage tumoricidal responses by platelet-activating factor.

Platelet-activating factor (PAF) has previously been shown to stimulate intracellular signal transductional events similar to the macrophage tumoricidal activators interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS). Macrophages stimulated with IFN-gamma and LPS utilize various cytolytic mediators in order to kill tumor cells. However, PAF has been shown to only induce and enhance tumor necrosis factor-alpha (TNF alpha)-mediated cytolysis by macrophages. Therefore, the purpose of this study was to determine whether PAF, in comparison with IFN-gamma and LPS, could stimulate macrophages for both TNF alpha- and non-TNF alpha-mediated tumoricidal activity. For this, the activation of macrophages for a cytolytic response was characterized by the production of TNF alpha and nitric oxide (NO2-), as well as, their ability to kill select tumor cells. PAF together with IFN-gamma stimulated macrophage secretion of NO2-. In addition, PAF enhanced IFN-gamma- and LPS-stimulated NO2- production. PAF, together with IFN-gamma, also activated macrophages for tumoricidal activity against TNF alpha-resistant tumor cells. In assays to determine the temporal sequence of activation, increased tumor cell cytolysis was observed only when macrophages were first treated with IFN-gamma. Moreover, PAF enhanced macrophage tumoricidal activity when added with LPS and IFN-gamma. With respect to TNF alpha production, macrophages activated with high concentrations of PAF stimulated significant levels of TNF alpha compared to macrophages without PAF. A similar level was observed following multiple additions of a lower concentration of PAF. Also, PAF induced macrophage cytolytic activity against a TNF alpha-sensitive tumor cell. In addition, PAF significantly enhanced LPS-induced TNF alpha production. Thus, PAF can play a modulatory role in the activation for non-TNF alpha-mediated tumoricidal activity of macrophages.

Animals↗

PubMed1995

Role of 5'-lipoxygenase metabolites in the activation of peritoneal macrophages for tumoricidal function.

Metabolites of arachidonic acid have been shown to be potent biological modulators of macrophage function. While the role of cyclooxygenase metabolites of arachidonic acid have been well studied, metabolites of lipoxygenase have not. In this report, we evaluate the role that select 5'-lipoxygenase (5'-LO) products may play in macrophage activation for select tumoricidal functions. When thioglycollate-elicited macrophages were treated with inhibitors of 5'-LO during activation, cytolytic capacity, nitric oxide production, and tumor necrosis factor-alpha production were significantly inhibited. Moreover, both an inhibitor of the 5'-LO-activating protein and an inhibitor of glutathione-s-transferase (GST) significantly decreased macrophage tumoricidal function. The activating agents used were able to stimulate 5'-LO activity which was measured by quantitating secreted LTC4. Increased production of PGE2 by shunting could have been the cause for decreased macrophage tumoricidal function. However, treatment of macrophages with inhibitors of 5'-LO during lipopolysaccharide stimulation did not increase formation of PGE2. When select 5'-LO metabolites were added to cultures during activation and 5'-LO inhibition, tumoricidal activity could not be restored, even when the metabolites were encapsulated in liposomes. These results suggest that the activity of 5'-LO and GST are important for macrophage activation. However, the specific role of 5'-LO metabolites has not been completely established.

Animals↗

PubMed1995

A novel phorbol ester from Excoecaria agallocha.

The novel phorbol ester 12-deoxyphorbol 13-(3E,5E-decadienoate) [1] was isolated as the anti-HIV principle of Excoecaria agallocha leaves and stems collected in northwest Australia. The structure was determined by spectral means. Compound 1 was also a potent displacer of [3H]-phorbol dibutyrate from rat brain membranes.

Animals↗

PubMed1995

Majapolene A, a cytotoxic peroxide, and related sesquiterpenes from the red alga Laurencia majuscula.

Seven new sesquiterpenes, majapolenes A [1] and B [2], majapolone [3], and majapols A [4], B [5], C [6], and D [7], were isolated from a Philippine collection of Laurencia majuscula. With the exception of majapolene B [2], all compounds were isolated as inseparable diastereomeric mixtures. Structure elucidation was achieved by spectroscopic methods. Majapolene A [1], a dioxabicyclo[2.2.2]-alkene, displayed modest activity in the NCI 60-cell line cytotoxicity screen. Majapolene A was also found as a major component of a Philippine collection of Laurencia caraibica.

Antineoplastic Agents↗

PubMed1995

Modulation of signal transduction in macrophages by dietary fatty acids.

Tumor growth can be altered by the amount and type of fat in the diet. Although there are several possible mechanisms for this, recent work suggests that alterations in the immune system by dietary fat may affect tumorigenesis. The focus of recent studies has been on dietary fat modulation of macrophage function because that cell plays a pivotal role in many immune responses, including anti-tumor activity. One possible mechanism of dietary fat effects on macrophages is altered signal transduction, which, in turn, could alter gene regulation and macrophage function. Initial studies tested the effects of dietary fat on kinase activity after stimulation with interferon-gamma. Macrophages from mice fed menhaden fish oil (MFO) had slightly decreased protein kinase C activity compared with macrophages from mice fed safflower oil (SAF). No differences among the diets were observed when the activity of protein kinase A and G were tested. When calcium mobilization was tested, we found that macrophages from mice fed MFO had an increased response compared with macrophages from mice fed SAF. Dietary fat also modified the response of macrophages to platelet-activating factor with respect to the induction of Ia expression. In studies to identify genes involved in dietary fat effects on macrophage function, we screened a cDNA library of macrophages treated with prostaglandin E2 (PGE2), a lipid-based mediator that can modulate macrophage function and be altered by dietary fat. The cloned gene, BTG1, was enhanced in macrophages treated with PGE2, but the relationship with dietary fat remains to be determined.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Development of an interleukin-2 receptor expression assay and its use in evaluation of cellular immune responses in bottlenose dolphin (Tursiops truncatus).

We describe optimization of a peripheral blood mononuclear leukocyte proliferation assay and development of an interleukin-2 receptor (IL-2R) expression assay for bottlenose dolphins (Tursiops truncatus). Peripheral blood mononuclear leukocytes obtained from both Sea World (February 1993) and the Naval Command Control and Ocean Surveillance Center (March 1993) (San Diego, California, USA) were stimulated with the mitogens concanavalin A (ConA) and phytohemagglutinin (PHA) and evaluated for optimum proliferation and IL-2R expression. Based on these optimization assays, standard conditions were established and used to assess immune function in a population of apparently healthy, free-ranging bottlenose dolphins from Sarasota Bay, Florida (USA) in June 1993. A positive correlation was observed between proliferation assays using ConA and PHA as the stimulants. However, IL-2R expression induced by both mitogens differed significantly.

Animals↗

PubMed1995

Blastogenesis and interleukin-2 receptor expression assays in the harbor seal (Phoca vitulina).

Two in vitro functional assays were developed to evaluate mitogen-induced responses of peripheral blood mononuclear leukocytes (PBML) from free-ranging harbor seals, Phoca vitulina. Lymphocyte proliferation was measured by a standard blastogenesis assay following optimization of culture conditions including mitogen concentration, cell density, and incubation time. These optimized parameters, with the exception of incubation time, were subsequently employed to measure lymphocyte activation by analytical flow cytometry using fluorochrome-based identification of cell surface interleukin-2 receptor (IL-2r) expression. Baseline values established for free-ranging harbor seals had extensive animal variability; there was evidence that the samples were derived from a group of animals with a normal distribution. Positive correlations were observed between blastogenesis assays, and between blastogenesis and activation assays, when using pokeweed or concanavalin A as the stimulus. However, no relationship was found in the expression of the IL-2r induced by these mitogens. This result supports the contention that the two mitogens stimulate different lymphocyte subpopulations. This was observed only with the IL-2r expression assay because of its unique ability to measure the number of T lymphocytes initially activated rather than the ultimate number of progeny cells identified by blastogenesis. Both assays, used concurrently, should provide a more comprehensive representation of lymphocyte competence and serve as a measure of animal health.

Animals↗

PubMed1994

The biologic window for chimeric L6 radioimmunotherapy.

BACKGROUND: There has been little success in using radioimmunotherapy in patients with adenocarcinoma, partly because of the low tumor uptake of the administered monoclonal antibody (MoAb). The authors recently reported therapeutic response in advanced cancer patients who received 131I chimeric-L6 MoAb. The L6 MoAb identifies abundant, nonshed antigen that is expressed in many human carcinomas, including carcinomas of the lung, breast, colon, and ovary. In vitro both mouse L6 (L6) and chimeric L6 (ChL6) mediate complement-dependent tumor cytolysis with human serum, and antibody-dependent tumor cell cytolysis with normal human peripheral blood mononuclear cells. The authors have used L6 or ChL6 for radioimmunotherapy to exploit their biologic activity to create a "therapeutic window" of increased vascular permeability, allowing more 131I MoAb to reach the tumor. A reactive target is present in the vascular endothelium but can be covered by unlabeled L6 or ChL6. METHODS: Nine patients with metastatic breast cancer were treated on a therapy protocol and received imaging and therapy doses of 131I ChL6 on two sequential days at 4 week intervals. During each treatment cycle, serum cytokines, complement, albumin, and 131I ChL6 blood clearance were monitored, peripheral blood mononuclear cell activation was assessed, and tumor uptake and response were documented. RESULTS: After L6 or ChL6 was infused, patients demonstrated immediate serum-complement activation, manifested by rapidly decreasing levels of serum complements 3 and 4. Tumor uptake of the second 131I MoAb (therapeutic) injection, given after the second daily injections of 200 mg MoAb, was usually higher than the tumor uptake of the first 131I MoAb (imaging) dose given after a single 200 mg infusion of MoAb. Although serum complement frequently decreased after the first 50-100 mg dose of L6 or ChL6, elevation of soluble interleukin-2 receptor (IL-2R) in serum was seen only in patients who received 150 mg or more of L6 or ChL6. In the nine treated patients, with only one exception, the higher grade of therapeutic tumor response was seen in patients with a greater increase in IL-2R levels. CONCLUSIONS: The clinical importance of understanding these mechanisms is emphasized by the occurrence of measurable tumor regressions in five of the first nine advanced metastatic breast cancer patients treated in this manner. Absence of pulmonary edema and delayed release of dose-dependent IL-2R suggest that targeting of the pulmonary endothelium by L6 or ChL6 is not the major cause of the observed biologic effects. This unique response of a solid tumor to radioimmunoconjugate therapy may be secondary to both the increased delivery of the radioimmunoconjugate to tumor cells caused by enhanced vascular permeability, and to synergistic effects of radiation and activated effector cell mechanisms.

Adult↗

PubMed1994

Alteration of tumor necrosis factor-alpha production by macrophages from mice fed diets high in eicosapentaenoic and docosahexaenoic fatty acids.

Dietary exposure to n-3 fats found in marine fish oils are known to reduce certain inflammatory conditions. Although depressed prostaglandin E2 (PGE2) production is thought to be a major mechanism of the beneficial effects, the direct effects of n-3 fatty acids on inflammatory macrophage function are not well understood. In this study, production of the inflammatory monokine, tumor necrosis factor-alpha (TNF alpha), by isolated murine macrophages was assessed following a 3-week feeding with diets containing either 10% menhaden fish oil as a source of n-3 fatty acids or, as a control and source of n-6 fatty acids, 10% safflower oil. Cultures of peritoneal macrophages from mice fed diets with n-3 fatty acids had more TNF alpha activity 24 hr after in vitro stimulation with bacterial lipopolysaccharide than did macrophages from mice fed the n-6-containing diet. The onset and maximal synthesis of bioactive TNF alpha and down-regulation of messenger RNA for TNF alpha appeared to be similar for the two diets, suggesting that macrophages from mice fed a diet high in n-6 but not n-3 fatty acids were capable of removing active TNF alpha from culture media. Experiments in which PGE2 was added exogenously indicated that the removal of TNF alpha from culture supernatant by macrophages was induced by lower concentrations of PGE2 than that associated with termination of production, and that n-3 fatty acid diets caused a selective loss in the clearance mechanism. These results demonstrate a specific alteration of PGE2-mediated regulation of macrophage-produced TNF alpha by n-3 fatty acids.

Animals↗

PubMed1994

A possible mechanism by which dietary fat can alter tumorigenesis: lipid modulation of macrophages function.

It has been known for at least 20 years that fatty acids can alter immune functions in vitro. More recently we have begun to understand the role that dietary fats play in immunity [formula: see text] and specifically how they may alter macrophage function. In the future it will be important not simply to redefine that fatty acids can alter select macrophage functions but to understand the mechanisms by which that occurs. Whether the same or different mechanisms are operational for those functions that are altered by dietary fat remains to be determined. Nevertheless, tumoricidal responses can be modified depending on the fatty acids in the diet. Hopefully, these recent observations will expand our understanding of how lipids regulate macrophage tumoricidal function and thus, might lead to new insights of how dietary fat may be manipulated to affect breast tumor regression.

Animals↗

PubMed1994

Effect of dietary linseed oil on tumoricidal activity and eicosanoid production in murine macrophages.

Diets that contain high levels of n-3 fatty acids from fish oil have been shown to significantly effect macrophage cytolytic capacity, tumor necrosis factor alpha production and eicosanoid production. The present study was undertaken to determine whether n-3 fatty acids from vegetable origin [linseed oil (LIN)] would have the same effects on murine macrophage tumoricidal capacity and eicosanoid production as would fish oil. Mice were fed for three weeks diets that contained 10% (wt/wt) of either LIN, which is high in linolenic acid (18:3n-3), menhaden fish oil (MFO), which is high in eicosapentaenoic (20:5n-3) and docosahexaenoic (22:6n-3) acids, or safflower oil (SAF), which is high in linoleic acid (18:2n-6). In vivo- or in vitro-activated macrophages were assessed for select functions. As expected, macrophages from mice fed LIN and MFO produced significantly lower levels of both prostaglandins and leukotriene C4 when compared with macrophages from mice fed SAF. In addition, LIN and MFO macrophages were able to synthesize leuko-triene C5, which could not be produced by macrophages from mice fed SAF. The effects of LIN, however, were not as pronounced as those of MFO. With respect to specific functions, macrophages from mice fed LIN did not have altered cytolytic capacity when compared with macrophages from mice fed SAF and activated in vitro with either lipopolysaccharide (LPS) alone for 24 h or with LPS plus interferon gamma (IFN gamma) for 5 h. Diet did not significantly alter tumoricidal capacity of macrophages activated completely in vivo either.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Implementing organized delivery systems: an integration scorecard.

Organized vertically integrated health systems are in a key position to play a major role in present health care reform efforts. To demonstrate a competitive advantage in the new health care environment, however, integration efforts must be successful. Based on a national study of nine organized delivery systems, this article develops measures of three types of integration that occur in vertically integrated health systems--functional, physician-system, and clinical. These measures can be used as a "scorecard" to assess progress toward achieving integration objectives.

Comprehensive Health Care↗

PubMed1993

Effects of in vitro exposure to arachidonic acid on TNF-alpha production by murine peritoneal macrophages.

Modifying the fatty acid composition of macrophages through diet can significantly alter some of their functions, such as tumoricidal capacity and tumor necrosis factor alpha (TNF-alpha) production. The mechanism of that modification, however, is unknown. In this report, we provide evidence that fatty acids added to macrophages in culture can significantly alter macrophage TNF-alpha production. For example when inflammatory macrophages were incubated with various doses of arachidonic acid [20:4(n-6)] during activation with lipopolysaccharide (LPS), we observed a dose-dependent decrease in the level of bioactive TNF-alpha with complete inhibition at 2-5 microM. This inhibition was specific for 20:4(n-6) because in vitro treatment with other fatty acids, such as eicosapentaenoic [20:5(n-3)] or docosahexaenoic [22:6(n-3)] acids, had differential effects. The inhibitory action of 20:4(n-6) did not involve toxicity because cell viability was not affected and in vitro interferon-gamma and lipopolysaccharide (LPS) activation of macrophages for killing of P815 tumor targets was not altered. Inhibition by 20:4(n-6) occurred posttranscriptionally, and could be reversed when macrophages were treated with indomethacin during activation. Arachidonic acid treatment also significantly increased the production of immunoreactive prostaglandin E2 (PGE2) by LPS-treated and untreated macrophages. These results suggest that in vitro treatment of macrophages with 20:4(n-6) may inhibit TNF-alpha production through an alteration in the levels of PGE2 at a posttranscriptional level. These results provide evidence that some dietary fats may affect macrophage activity through modification of eicosanoid synthesis.

Animals↗

PubMed1993

Kahukuenes, new diterpenoids from the marine alga Laurencia majuscula.

Kahukuenes A [4] and B [5], new diterpenoids possessing an unprecedented prenylated chamigrene structure as part of a decalin ring, were isolated from the Hawaiian marine alga Laurencia majuscula. Spectroscopic methods, including extensive 1D and 2D nmr studies, were used to establish the structure and relative stereochemistry of these two secondary metabolites.

Bridged Bicyclo Compounds↗