Search PubMed⌕ Search

Biomedical subjects

W B Ershler

Publications and source records attributed to W B Ershler.

At least 37 records · Page 2Linked to original sources
PubMed1996

Inhibition of NFkappaB activity through maintenance of IkappaBalpha levels contributes to dihydrotestosterone-mediated repression of the interleukin-6 promoter.

Androgens repress expression of many genes, yet the mechanism of this activity has remained elusive. The cytokine, interleukin-6, is active in a variety of biological systems, and its expression is repressed by androgens. Accordingly we dissected the mechanism of androgen's ability to inhibit interleukin-6 expression at the molecular level. In a series of co-transfection assays, we found that 5alpha-dihydrotestosterone, through the androgen receptor, repressed activation of the interleukin-6 promoter, in part, by inhibiting NFkappaB activity. It did not appear that 5alpha-dihydrotestosterone inhibited NFkappaB by activating the androgen receptor to compete for the NFkappaB response element as we could not detect androgen receptor binding to the IL-6 promoter by DNase I footprinting assay. However, by electrophoretic mobility shift assay we found that 5alpha-dihydrotestosterone repressed formation of NFkappaB middle dotNFkappaB response element complex formation. In LNCaP prostate carcinoma cells, 5alpha-dihydrotestosterone achieved this effect through maintenance of IkappaBalpha protein levels in the face of phorbol ester, a stimulus that results in IkappaBalpha degradation. Finally, we confirmed that IkappaBalpha inhibits NFkappaB-mediated activation of the interleukin-6 promoter. These data suggest that maintenance of IkappaBalpha levels may represent the first identified mechanism for androgen-mediated repression of a natural androgen-regulated gene.

Cell Line↗
PubMed1996

The androgen receptor: a mediator of diverse responses.

Androgens mediate a number of diverse responses through the androgen receptor, a 110 kD ligand-activated nuclear receptor. Androgen receptor expression, which is found in a variety of tissues, changes throughout development, aging, and malignant transformation. The androgen receptor can be activated by two ligands, testosterone and dihydrotestosterone, which bind to the androgen receptor with different affinities. This difference in binding affinity results in different levels of activation of the androgen receptor by the two ligands. The androgen receptor acts as a transcriptional modifier of a variety of genes by binding to an androgen response element. The ability to confer androgen specific actions by the androgen response element may depend on other cell-specific transcription factors and cis-acting DNA elements in close proximity to it. Testosterone and dihydrotestosterone appear to act upon an identical nuclear receptor. However, in certain instances, they mediate different physiologic responses. For example, dihydrotestosterone, but not testosterone, is capable of mediating full sexual development of the male external genitalia. In some cases, the androgen receptor may induce opposite physiologic responses in similar tissue types depending on their location. For example, in male pattern baldness, activated androgen receptors may suppress the growth of distinct hair follicle populations through initiating stromal-epithelial actions, whereas other hair follicles continue to proliferate. In other cases, altered androgen receptor activity due to its mutation or altered expression may lead to pathology such as recurrence of prostate cancer due to development of androgen independence allowing tumor cell proliferation under androgen deprivation.

Androgens↗
PubMed1996

Surgical and psychological stressors differentially affect cytolytic responses in the rhesus monkey.

Four experiments were conducted in aged rhesus monkeys to investigate how physical and psychological stressors influence the lymphocyte cytolytic responses against two target cell lines. An initial analysis of the lytic activity of various cell subsets against K562 and RAJI target cell lines suggested that both CD3+CD8+ and several CD3- subsets were responsible for lysis of the K562 cells. The RAJI cell line, in contrast, was killed primarily by CD3-subsets. To explore the implications of this differential mediation of lysis, cytolytic activity was evaluated after a physical challenge (surgery), a psychological disturbance (social separation), and in vitro incubation of lymphocytes with cortisol. The minor surgical procedure-laparoscopic examination-resulted in a significant decrease in lymphocyte cytolytic responses against both target cells 1 week postsurgery. In contrast, psychological disturbance elicited by changes in social relations caused a dual response, differentially affecting the lysis of either K562 or RAJI cells, dependent upon the type of behavioral reaction. Incubation of lymphocytes with cortisol in vitro indicated that lysis of both targets could be affected by corticosteroids, but the high concentration required (10(-6) M) suggested that the in vivo inhibition of cytotoxicity may not have been mediated by adrenocortical activation. Overall, the results highlight the value of utilizing multiple target cell systems in the analysis of cytolytic activity, especially in studies using nonhuman primates.

Animals↗
PubMed1996

Prenatal endocrine activation alters postnatal cellular immunity in infant monkeys.

Cellular immune responses were evaluated in 35 infant rhesus monkeys generated from two types of pregnancy conditions. Pregnant females were administered either saline or adrenocorticotropic hormone (ACTH) for 2 weeks between Days 120 and 133 postconception, approximately 1 month before parturition. After birth, lymphocytes obtained from infants in the ACTH condition failed to respond as readily to allogeneic cells in mixed lymphocyte cultures, proliferated less to Con A, exhibited lower suppressor function following stimulation with Con A, and showed lower cytolytic activity against target cells. For some measures, the prenatal effect was observed more consistently in male infants. Differences were evident with these in vitro immune assays through 6 months of age, indicating that acute disturbance during the prenatal period can have lingering effects on postnatal immunity.

Adrenocorticotropic Hormone↗
PubMed1996

Reduced immune responses in rhesus monkeys subjected to dietary restriction.

Dietary restriction (DR) has emerged as a major paradigm in experimental gerontology. The effects of DR on rodents are numerous and include reduced rates of immunologic aging, delayed morbidity, and increases in longevity. The effects of DR on primate species remain largely unknown. We began a randomized trial of long-term, adult-onset DR in rhesus monkeys (Macaca mulatta) in 1989. This report describes some early differences in immunologic function after two to four years of DR. Peripheral blood mononuclear cells were studied for mitogen-induced proliferation, natural killer (NK) cell lysis, and expression of cell surface antigens. Antibody response to influenza vaccine and the number of peripheral blood lymphocytes were also measured. Unexpectedly, concanavalin A and pokeweed mitogen response measures were reduced in restricted monkeys compared to controls (p < or = .01). NK activity and antibody responses were also reduced (p < .05). Neither cell surface antigens nor peripheral blood lymphocyte counts appear affected by DR thus far.

Aging↗
PubMed1995

Effect of IL-6 receptor antisense oligodeoxynucleotide on in vitro proliferation of myeloma cells.

IL-6 stimulates proliferation of various tumors, including lymphoma and myeloma; thus, inhibiting IL-6 may decrease the growth of these tumors. Accordingly, we examined the effect of IL-6 and IL-6R antisense phosphorothioated oligodeoxynucleotides (ODNs) on proliferation of IL-6 responsive (U266) and nonresponsive (RPMI 8226) myeloma cell lines. Cells were grown in the presence or absence of IL-6, with added antisense to either IL-6 or IL-6R. Cells were evaluated for proliferation ([3H]thymidine uptake) and steady state levels of both IL-6 and IL-6R mRNA by competitive PCR (C-PCR). Proliferation of U266 cells was decreased markedly by IL-6 antisense ODN in the absence of IL-6, but not in its presence. In contrast, IL-6R antisense ODN inhibited proliferation of U266 cells in both the presence and absence of IL-6. As anticipated, neither IL-6 nor IL-6R antisense ODN had an effect on RPMI 8226 proliferation. C-PCR demonstrated a marked and specific decrease of IL-6 and IL-6R mRNA in cells exposed to IL-6 ODN and IL-6R ODN, respectively. These results suggest that IL-6R antisense ODN may be a more effective inhibitor of IL-6-stimulated cells than IL-6 antisense in a therapeutic setting.

Base Sequence↗
PubMed1995

In vivo cytokine gene transfer by gene gun reduces tumor growth in mice.

Implantation of tumor cells modified by in vitro cytokine gene transfer has been shown by many investigators to result in potent in vivo antitumor activities in mice. Here we describe an approach to tumor immunotherapy utilizing direct transfection of cytokine genes into tumor-bearing animals by particle-mediated gene transfer. In vivo transfection of the human interleukin 6 gene into the tumor site reduced methylcholanthrene-induced fibrosarcoma growth, and a combination of murine tumor necrosis factor alpha and interferon gamma genes inhibited growth of a renal carcinoma tumor model (Renca). In addition, treatment with murine interleukin 2 and interferon gamma genes prolonged the survival of Renca tumor-bearing mice and resulted in tumor eradication in 25% of the test animals. Transgene expression was demonstrated in treated tissues by ELISA and immunohistochemical analysis. Significant serum levels of interleukin 6 and interferon gamma were detected, demonstrating effective secretion of transgenic proteins from treated skin into the bloodstream. This in vivo cytokine gene therapy approach provides a system for evaluating the antitumor properties of various cytokines in different tumor models and has potential utility for human cancer gene therapy.

Animals↗
PubMed1995

Effects of early rearing environment on immune responses of infant rhesus monkeys.

In animals, perturbations of the rearing environment have been shown to alter behavior, cognition, and physiology, including immune responses. In order to evaluate the effect of early rearing conditions on the development of immune responses in the infant primate, several immunological measures were assessed in rhesus monkey infants, nursery-reared (NR) or mother-reared (MR), from birth to 2 years of age. Rearing in the absence of the mother affected several aspects of cellular immunity. NR monkeys had significantly lower proportions of CD8 cells and lower natural killer cell activity than did MR monkeys. In contrast, their lymphocyte proliferation responses to mitogen stimulation were higher than those of MR monkeys. An attempt to behaviorally rehabilitate the NR infants at 1 year of age did not result in a recovery of normal immune responses. This study indicates that abnormal early rearing may have long-lasting effects on the immune system, which could have health consequences later in life.

Animal Husbandry↗
PubMed1995

Elevated plasma levels of interleukin-6 in postmenopausal women do not correlate with bone density.

OBJECTIVE: To determine if plasma levels of Interleukin-6 (IL-6) across the lifespan correlate with bone density or plasma osteocalcin. DESIGN: Cross-sectional study. PARTICIPANTS: Forty-five healthy community-dwelling volunteers aged 25-74 years. Exclusion criteria were smoking use of medications known to affect bone metabolism (corticosteroids, heparin, thyroxine, thiazides, and anticonvulsants), and presence of chronic inflammatory disease. MEASUREMENTS: Bone density was measured by dual-energy X-ray absorptiometry at the femoral neck and lumbar spine. Plasma levels of IL-6 and osteocalcin were determined by ELISA and RIA, respectively. RESULTS: Plasma levels of IL-6 increased with advancing age (P < .0001) and correlated with postmenopausal status (P < .0001). No correlation was observed between plasma IL-6 level and bone mineral density at either the lumbar spine or femoral neck, and none was observed with plasma osteocalcin. CONCLUSIONS: The elevation of plasma IL-6 observed following menopause is consistent with the proposed importance of estrogen in the regulation of IL-6. These findings do not provide support for a role of IL-6 in determination of peak bone density or subsequent development of osteoporosis. However, it is possible that plasma levels of IL-6 differ from those in the bone microenvironment.

Absorptiometry, Photon↗
PubMed1994

Dietary restriction from middle age attenuates age-associated lymphoma development and interleukin 6 dysregulation in C57BL/6 mice.

Dietary restriction (DR) started in middle age profoundly reduces the occurrence of lymphoma in C57BL/6 mice. Here, we report immunocellular and molecular changes associated with this mode of cancer prevention. Twelve-month-old male C57BL/6 mice were either fed a control diet or subjected to moderate DR (approximately 25% < control intake). DR significantly reduced lymphoma development (incidence at 25 months, 19% of 72 control mice versus 5% of 60 DR mice). Flow cytometry of splenocytes showed that DR increased the percentage of CD4+ and CD8+ cells. Lymphomatous spleens displayed varied labeling patterns and high percentages of cells in S phase. Splenocyte c-myc expression tended to increase with age in controls and was reduced by DR. Lymphopenia and markedly reduced nucleated cell yields from peripheral lymphoid tissues were induced by DR. Serum interleukin 6 levels increased with age and were quite high (> 2500 pg/ml) in several mice with lymphoma and other histopathological findings. DR attenuated this age-associated increase. Immunohistochemical studies of lymphomatous spleens showed the presence of interleukin 6 in monocytic appearing cells but not in lymphoma cells. These observations support the possibility that an age-associated interleukin 6 dysregulation is important in lymphomagenesis.

Age Factors↗
PubMed1994

Bidirectional effects of interleukin-1 on immune responses in rhesus monkeys.

Physiological and pharmacological doses of recombinant human interleukin-1 (IL-1) were administered intravenously to juvenile rhesus monkeys in order to evaluate its effects on immune and endocrine activity. Mitogen-induced lymphocyte proliferation was increased following 1-ng and 1-microgram doses of IL-1, but decreased following 10- and 50-micrograms doses. Natural killer cell cytotoxicity was also significantly reduced at the 10-micrograms dose and tended to be below baseline at the 50-micrograms dose. These changes were associated with marked neutrophilia observed after administration of IL-1. These results indicate that peripheral administration of IL-1 can either enhance or inhibit the numbers and responses of immune cells in rhesus monkeys depending on the dose administered. These responses may have been the result of differential activation of the endocrine system, because levels of pituitary hormones in plasma increased progressively with increasing doses of IL-1. Thus, the extent to which a particular dose of IL-1 induces the release of pituitary-adrenal hormones may be related to the direction and magnitude of the resulting changes in immune activity.

Adrenocorticotropic Hormone↗
PubMed1994

Efficacy of an influenza hemagglutinin-diphtheria toxoid conjugate vaccine in elderly nursing home subjects during an influenza outbreak.

OBJECTIVE: To compare the efficacy of an influenza hemagglutinin-diphtheria toxoid conjugate vaccine with the commercially available influenza hemagglutinin-subunit vaccine in preventing influenza in older adults living in a nursing home. DESIGN: A prospective, randomized, double-blind vaccine trial with 5 months of follow-up after vaccination. SETTING: Fourteen Wisconsin nursing homes. PARTICIPANTS: Nursing home residents at least 65 years old who were able to give informed consent and were free of malignancy and not receiving immunosuppressive therapy. INTERVENTIONS: Participants received, by intramuscular injection, 0.5 mL of a trivalent influenza vaccine containing 15 micrograms each of A/Leningrad/360/86 (H3N2), A/Taiwan/1/86 (H1N1), and B/Ann Arbor/1/86 (HA) or 0.5 mL of an influenza vaccine containing the same antigens conjugated to diphtheria toxoid (HA-D). MEASUREMENTS: Blood was obtained pre- and 1 month post-vaccination to assess for any vaccine-induced antibody titer change. Clinical surveillance for respiratory illness was performed twice weekly for 5 months. A record was kept of all signs and symptoms of new respiratory illness, and a viral culture and acute and convalescent sera were obtained. RESULTS: 204 participants received HA and 204 received HA-D. Both groups had similar baseline antibody levels to all influenza antigens. HA-D recipients seroconverted more frequently based on serum neutralizing activity (P < 0.05), had a greater increase in geometric mean titer (GMT), and sustained the increase in antibody titer longer than HA recipients. Vaccine hemagglutinin recall was greater in a subset of HA-D recipients as measured by lymphocyte proliferative assays (P < 0.05). During an outbreak of influenza A (H3N2 A/Shanghai/11/87-like and A/Victoria/7/87-like), fewer HA-D (29/195) than HA (43/204) recipients had laboratory-confirmed infection (P = 0.053), and, of these, fewer HA-D-treated subjects had lower respiratory tract involvement (5/29 HA-D and 17/43 HA) (P = 0.022). CONCLUSIONS: HA-D was more immunogenic in institutionalized elderly recipients and produced greater protection from influenza infection. Superior protection may be due to HA-D's ability to stimulate and recruit antigen-presenting cells, thus enabling the recipient to achieve and maintain functional antibody titers.

Aged↗
PubMed1994

The role of interleukin-6 in certain age-related diseases.

Interleukin-6 (IL-6) is a pro-inflammatory cytokine with a wide range of functions. Perhaps the most important physiologically is its role as a mediator of the acute phase inflammatory response. Normally, there is little measurable IL-6 in the circulation, but levels increase abruptly to nanogram amounts during an inflammatory process. During aging, it has been proposed that the tight regulation of IL-6 gene expression becomes less effective and levels are measurable even when there is no evidence for inflammation. Several investigators have identified this cytokine as being involved in the pathogenesis of various disease processes and we have suggested that certain age-associated diseases are directly related. Among these are late-life lymphoma and myeloma, osteoporosis and possibly Alzheimer's disease.

Aging↗
PubMed1994

Effects of recombinant human interleukin-6 administration on bone in rhesus monkeys.

The role of interleukin-6 in the bone microenvironment is controversial. We studied the effect of recombinant human interleukin-6 (rhIL-6) administration on bone metabolism in 10 adult female rhesus monkeys (age 12-27 years). Monkeys received rhIL-6 (15 micrograms/kg/day) daily by subcutaneous injection for 28 days. Serum alkaline phosphatase, osteocalcin, and 24 h urinary calcium excretion were determined before, during (at weeks 2 and 4), and after (at week 6) treatment. Transilial biopsies (right and left) were obtained before treatment was initiated and just after the final (28th) dose at week 4. The serum alkaline phosphatase significantly increased at 2 and 4 weeks of rhIL-6 administration. Osteocalcin and urinary calcium excretion significantly decreased at week 2. Upon treatment with rhIL-6 significant reductions in OS/BS and Ob.S/BS were observed without changes in other static histomorphometry parameters. The reductions in urinary calcium excretion, serum osteocalcin, and the static bone parameters are consistent with an IL-6 induced reduction in bone formation or turnover. Whether this pharmacologic effect is relevant at the physiologic level remains to be determined.

Alkaline Phosphatase↗
PubMed1993

Altered regulation of IL-6 production with normal aging. Possible linkage to the age-associated decline in dehydroepiandrosterone and its sulfated derivative.

Normal aging in humans has been recently shown to be accompanied by reduced control over production of the multifunctional cytokine IL-6. This cytokine was reported to be quantitatively elevated in most serum samples obtained from "normal" elderly humans. In the present investigation, we report that IL-6 levels are elevated in serum samples obtained from aged mice, and its spontaneous production could also be easily detected in culture supernatants of unstimulated lymphoid cells obtained from aged, but not mature, adult donors. Spontaneous production of IL-6 was consistently observed in culture supernatants of lymphoid cells from both the spleen and mesenteric lymph nodes from aged donors, but was absent from supernatants derived from their peripheral lymph nodes. In aged mice, the reduced regulation of IL-6 production could be effectively prevented and/or reversed by supplementing aging animals with dehydroepiandrosterone sulfate, a steroid hormone whose endogenous production is known to decline with advancing age in all species tested. It was also established that serum obtained from old dehydroepiandrosterone sulfate-treated mice contained lower (normal) levels of serum amyloid P substance (an acute phase reactant), reduced levels of serum Ig (all classes and isotypes) and lower titers of tissue-specific autoantibodies than untreated aged controls. Therefore, a number of well described, age-related conditions, some of which could be contributing to the pathologic phenotype of old age, may actually represent secondary effects to this age-associated change in IL-6 production.

Aged↗
PubMed1993

Dietary restriction of adult male rhesus monkeys: design, methodology, and preliminary findings from the first year of study.

Dietary restriction (DR) retards aging processes and extends maximum life span in rodents and in simpler animals. We initiated a study in 30 adults (8-14 years old) male rhesus monkeys to determine whether or not aging processes are retarded by adult-onset DR in a primate species and herein report results from the experiment's first year. Following a 3-6 month period when baseline data were obtained, 15 animals were assigned to a control group and given free access to a semipurified diet for 6-8 hours per day. The other 15 monkeys were fed the same diet but at 70% of their baseline intake levels predetermined individually. The animals are being evaluated semi-annually for body size and composition, physical activity, metabolic rate, glucose tolerance and insulin sensitivity, hematologic indices, immunologic function, and fingernail growth. Ocular function is assessed annually. The preliminary observations after one year are: (a) all monkeys appear to be in excellent health; (b) average body weights for controls increased by 9% while monkeys on DR did not gain weight; (c) monkeys on DR have less body fat than do control monkeys, whereas the amount of lean body mass has not been significantly influenced by DR; (d) there was a small but statistically significant reduction in physical activity for monkeys on DR relative to controls; and (e) DR has not overtly influenced the other measures. Control monkeys gradually reduced their voluntary levels of food intake during the first year of study, and food allotments to DR monkeys are being adjusted accordingly in order to reinstate the intended 30% difference between groups. These early data indicate that DR can be safely instituted in adult monkeys, but that longer term and/or more severe DR is required to determine if it is capable of influencing age-sensitive indices in long-lived primates.

Accommodation, Ocular↗
PubMed1993

The influence of an aging immune system on cancer incidence and progression.

The majority of cancers occur in patients over the age of 65 years, and yet the important interactions of normal aging upon the neoplastic process remain to be thoroughly explored. For example, there is no unifying and conclusive explanation for the increased risk of cancer with advancing age. The age-associated decline in immune function has previously been implicated in this regard. However, it is likely that other factors, such as the time it takes to proceed through the multistep neoplastic process, and the combined influence of age-associated increased susceptibility to carcinogen and decreased DNA repair are more important. Nevertheless, immune senescence does influence various aspects of tumor growth and spread. In this article these aspects are reviewed.

Aged↗