Search PubMed⌕ Search

Biomedical subjects

P H Black

Publications and source records attributed to P H Black.

At least 19 recordsLinked to original sources
PubMed1996

Endogenous substance P mediates cold water stress-induced increase in interleukin-6 secretion from peritoneal macrophages.

Previous studies from this laboratory had shown that exposure of mice to cold water stress leads to an increase in the secretion of interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF alpha) from their peritoneal macrophages. We now report that the secretion of IL-6 from peritoneal macrophages is also increased after cold water stress and that the peptide substance P (SP) participates in this stress-induced response. The stress paradigm involved subjecting male C57BL/6J mice to 5 min swim tests in 10 +/- 2 degrees C water twice daily for 4 d. Cold water stress augments the lipopolysaccharide-induced IL-6 secretion from peritoneal macrophages, elevates immunoreactive SP (iSP) in the peritoneal wash fluid, and reduces iSP in certain peritoneum-containing tissues or organs (i.e., diaphragm, abdominal wall, ileum, and rectum). The 10 d stress time studies indicate that increased IL-6 secretion is positively related to elevated iSP in the peritoneal wash fluid and inversely related to reduced iSP in certain peritoneum-containing tissues. Pretreatment with capsaicin, which depletes SP in the sensory nerve endings, eliminates stress-control differences in the peritoneal wash fluid and in certain peritoneal tissues. Moreover, RP67,580, a specific SP antagonist, eliminates the cold water stress-induced augmentation of IL-6 secretion from peritoneal macrophages. These results suggest that cold water stress promotes the release of SP from peritoneal tissues into the peritoneal cavity, where it participates in the cold water stress-induced macrophage functional alterations.

Analgesics↗
PubMed1995

Substance P and stress-induced changes in macrophages.

The present paper further links nervous-endocrine-immune systems by describing influences of SP on the immune system, and more specifically, on macrophage function. We have discussed how macrophages are important to immune responses in that much of cellular and humoral responses depend on macrophage function. Macrophages are sensitive to stress in that cold-water stress causes increased cytokine production, either spontaneously (IL-1), or after induction with LPS (IL-6, TNF alpha). Increased cytokine levels (IL-1, IL-6) may induce acute phase reactants in the liver, which is presumably the mechanism operative in the studies indicating increases in acute phase reactants after certain stressors in animals. SP is a likely candidate to affect immune function. Previous data show that macrophages from various species have receptors for and respond to SP in vitro. SP stimulates phagocytic and chemotactic capacity, as well as increased cytokine, PGE2, and thromboxane B2 production. SP is also involved in neurogenic inflammation and is likely to be involved in the pathogenesis of several inflammatory diseases. Present data indicate SP's involvement in macrophage responses to stress. We have shown that stress induced differential SP receptor binding to peritoneal macrophages, although the precise nature of binding differences has not yet been clearly elucidated. Stress also induces more immunoreactive SP in the peritoneal fluid that bathes the peritoneal macrophages. We hypothesize that the two events, altered SP binding and concomitant increased ligand, are causally related. In addition to other correlational data showing concomitant increased SP binding plus ligand concentrations, there is more direct evidence that SP ligand may induce SP receptor expression since the SP antagonist, CP-96,345, prevents the induction of SP receptor mRNA in the staphylococcal toxin A-induced gastroenteritis (C. Pothoulakis and S. E. Leeman, personal communication). Further supporting our notion for a causal relationship we have found the elimination of SP in vivo (via capsaicin pretreatment) reduced SP binding, as has been previously reported. We have also examined the role of SP on stress-induced altered macrophage function in vitro. SP greatly enhanced the LPS-induced macrophage TNF alpha production from stressed animals; in contrast, it produced relatively little effect on macrophages from control animals. Capsaicin pretreatment diminished the enhanced cytokine production in response to stress, such that levels of TNF alpha and IL-6 approximated those of control mice. Taken together, past and present data suggest that (1) stress may initiate, or at least contribute to, an inflammatory response, and that (2) SP is involved in the macrophage stress response. SP has long been known to be involved in inflammatory processes; our data further suggest its role in mediating stress-induced cytokine alterations.

Animals↗
PubMed1994

Central nervous system-immune system interactions: psychoneuroendocrinology of stress and its immune consequences.

Psychoneuroimmunology is a relatively new discipline which deals with CNS-immune system interactions. The evidence for such interactions was reviewed, as was the neuroendocrinologic response to stress. Recent evidence indicates that the behavioral, nervous system, and neuroendocrine responses to stress are mediated by hypothalamic CRF, which acts on both the sympathetic nervous system and the HPA axis, resulting in increased levels of corticosteroids, catecholamines, and certain opiates, substances which are generally immunosuppressive. Concentrations of growth hormone and prolactin, which are immunoenhancing, are elevated early during the response to stress but are later suppressed. Although several other neuromediators may also be released with stress, the net effect of a variety of acute stressors is down regulation of the immune system function. In the following minireview, I consider whether stress alters the resistance of the host to infection as well as the immunomodulatory effects of released immune system mediators on the brain.

Animals↗
PubMed1994

Immune system-central nervous system interactions: effect and immunomodulatory consequences of immune system mediators on the brain.

A bidirectional circuit exists between the central nervous system and the immune system, since activation of the immune system results in the elaboration of cytokines and inflammatory mediators; these mediators induce hypothalamic CRF, which stimulates the release of the same immunosuppressive molecules that mediate the response to stress. The brain, therefore, is likely to be involved in immune system regulation. Hypofunctioning of the HPA axis with insufficient down regulation may be involved in autoimmune or other diseases with excessive immune system activation. Hyperfunctioning of the HPA axis, which is not appropriately suppressed, has been found in a large number of patients with major depression. Evidence that stress is an important factor in both lowering resistance to infectious agents and contributing to the reactivation of latent viruses is discussed. Also discussed is the evidence that stress induces proinflammatory cytokines which may contribute to both the pathogenesis of inflammatory diseases of unknown etiology and the progression of HIV infection to AIDS by activation of HIV replication.

Adjuvants, Immunologic↗
PubMed1992

The effect of changes in thiol subcompartments on T-cell colony formation and cell cycle progression: relevance to AIDS.

Recently, it has been shown that intra- and extracellular thiol levels are significantly lower than normal even in the relatively early stages of human immunodeficiency virus (HIV) infection. It is plausible that this deficiency could contribute both to the loss of T-cell function and the ability to replenish T cells associated with HIV infection. We had previously reported that the T-cell colony-forming cell (T-CFC) is impaired in HIV infection and that it can be enhanced with the thiol compounds 2-mercaptoethanol (2-ME) and N-acetylcysteine (NAC). In this study, the effect of the thiol-depleting reagents buthionine sulfoximine, cyclohexene-1-one, and copper phenanthroline on T-CFC formation and cell cycle progression was determined in HIV+ subject and/or controls. All three reagents inhibited T-CFC formation and cell cycle progression with a suggestion that colony formation by cells from HIV+ subjects was more sensitive to the effects of thiol depletion. 2-ME and NAC enhanced effect of NAC did not appear to involve increased protein kinase C translocation. Our results suggest that oxidation of membrane thiols, as well as depletion of intracellular glutathione, inhibits T-CFC formation as well as cell cycle progression for mitogen-stimulated cells in bulk culture.

Acetylcysteine↗
PubMed1991

Biological measures and cellular immunological function in depressed psychiatric inpatients.

Thirty depressed psychiatric inpatients, including 18 with a diagnosis of major depression, and 25 hospital staff controls were compared with respect to cellular immune function--that is, mitogen responsiveness to concanavalin A (con A), phytohemagglutinin (PHA), and pokeweed mitogen (PWM); natural killer cell (NK) activity; and T cell subsets, including helper/inducer T cells (CD4) and suppressor/cytotoxic cells (CD8). Only physically healthy subjects, who had not used psychoactive medications (except for low dose benzodiazepines) or other medications known to affect the immune system for at least 14 days, were included. Paired comparisons of the immune measures of patients with a DSM-III diagnosis of major depression (n = 18) with their controls demonstrated a statistically significant reduction of the patients' con A response. In addition, the patients with major depression had significantly lower con A and PHA responses than the combined patients with other forms of depression (atypical, dysthymic, or atypical bipolar). There was no indication that severity of depression, dexamethasone suppression test status, benzodiazepine use, or age accounted for the differences in immune function. A possibly important, unexpected finding was that antihistamine use was associated with lower immune function.

Adult↗
PubMed1990

Effect of retinoic acid on tumor-mediated immunologic alterations in mice bearing a variant of the B16 melanoma.

This investigation examined the effect of retinoic acid on tumor progression and immunological status of mice bearing the B16-F10 melanoma (previously selected for high lung-colonizing capacity). Tumor cells were implanted s.c. in syngeneic C57BL/6 mice, half of which were treated with beta-all trans retinoic acid (RA). Although RA failed to exhibit direct toxicity on this variant at the concentration used, the immunologic aberrations induced by the tumors were diminished by i.p. RA administration (at 45 micrograms twice/week for 3 weeks). In mice bearing B16-F10 tumors, tumor burdens were decreased from 2.9% of body weight to 1.6%. The mitogenic responses of splenic lymphocytes to concanavalin A (ConA) were increased in tumor-bearing mice following this RA treatment. The presence of these tumor cells decreased the absolute number of CD4- and CD8-positive splenic lymphocytes. Following RA treatment, the CD8-positive population was increased in tumor-bearing mice, while the CD4+ population was not significantly altered. Since previous studies indicated that plasma membrane fragments (or vesicles) could alter lymphocyte distributions and proliferative capacities, the in vitro shedding of membrane fragments from B16-F10 tumor cells was assayed and observed to be decreased after continuous treatment of cultures with 10(-6) M RA for 21 days. Membrane shedding from B16-F10 cells was inhibited by 48.5% following RA treatment. Based on these in vivo and in vitro results, we suggest that RA treatment may diminish tumor growth by decreasing tumor-induced immunosuppressive events.

Animals↗
PubMed1990

Immunosuppression in mice induced by cold water stress.

A number of studies indicate that stress can result in suppression of the immune system in animals and man. Most of the studies have focused on alterations of lymphocyte function while only a few have investigated alterations of macrophage function or macrophage cytokine production. Macrophages play an essential role in homeostasis of the immune response. Indeed, the earliest events of the immune response occur in cells of the monocytic lineage, and their secretion of various cytokines may have both immunological and nonimmunological effects. The present studies were undertaken to determine whether alterations in macrophage physiology occur in mice subjected to a stress stimulus. Our studies in mice exposed to cold water stress for 4 days indicated reduced numbers of thymocytes and splenocytes, decreased T-cell blastogenesis, and reduced NK activity. Examination of elicited peritoneal macrophages from stressed mice revealed increased prostaglandin E2 (PGE2) secretion and decreased immune region associated antigen (Ia) expression in response to interferon-gamma. Despite elevated PGE2 levels, indomethacin was generally unable to restore depressed immune function. Of special interest was the finding that cell-associated and secreted interleukin 1 were significantly higher from unstimulated elicited macrophages from stressed mice. These results suggest that early in the response to stress, functions of a variety of cells within the immune system, especially macrophages, are altered and that dysregulated macrophage function may well contribute to the generalized suppression of the immune response in cold water stressed mice.

Animals↗
PubMed1990

Alterations of cellular characteristics of a human ovarian teratocarcinoma cell line after in vitro treatment with retinoids.

Differentiation of the human teratocarcinoma derived cell line. PA-1, with retinoids was examined at concentrations (10(-6)-10(-8) M) that did not exhibit an antiproliferative effect during log-phase growth. Treatment with naturally occurring retinoic acid or certain synthetic retinoids (13-cis retinoic acid, Ro10-9359, and Ro13-7410), while not significantly altering the log-phase growth rate, decreased the saturation cell density and mitotic indices after confluence. Retinoid treatment also induced changes in cell morphology, which appear to be related to reorganization of microtubules and microfilaments. Following retinoid treatment, the expression of cell glycoproteins (of 162 kDa, 152 kDa, 143 kDa. and 51 kDa) was altered. Treated cells also exhibited decreased expression of alkaline phosphatase, as well as an increased capacity for intercellular communication as evidenced by gap-junctional transfer of the phosphorylated toxic intermediate of 6-thioguanine to HPRT- cells. Treatment with retinoic acid dramatically reduced the quantity of shed plasma membrane material and altered its composition.

Alkaline Phosphatase↗
PubMed1989

Psychological and immunological associations in men with AIDS pursuing a macrobiotic regimen as an alternative therapy: a pilot study.

A group of men with AIDS who chose to follow a macrobiotic regimen as an alternative form of therapy was studied for the possible influence of psychological factors on their clinical progression. In this group, men with Kaposi's sarcoma (KS) had an estimated survival time of 60% at 3 years. Moreover, there was a tendency for lymphocyte number to increase during the first 3 years following diagnosis with KS. A subset of eight of these men with KS and one man with Pneumocystis carinii pneumonia (PCP) agreed to fill out a battery of psychological questionnaires. The results suggest low levels of fatigue, negative affect, and confusion, but high levels of vigor in this subgroup. Additionally, there was significant positive associations of CD4 positive lymphocyte numbers with trait curiosity and hardiness scores and significant negative associations with anxiety and depression. Mitogen responsiveness followed a similar pattern, but only a positive association with curiosity reached significance. Caution has to be used in interpreting such data, especially in view of the size of the sample and the complexity of the cohort. Nonetheless, these findings clearly suggest the need for prospective studies on the influence of psychological factors on the progression of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Increased T-cell colony formation in AIDS patients treated with zidovudine: a possible mechanism for increased lymphocyte number.

Treatment of AIDS patients with zidovudine is associated with an increase in lymphocyte counts. The mechanism for this increase is unclear and somewhat surprising in view of the myelosuppressive effect of zidovudine. To investigate this further, we measured lymphocyte numbers, T-cell subsets, and the ability of peripheral blood mononuclear cells (PBMC) to form T-cell colonies (T-CFC) in agar formation, in a group of patients with AIDS, before and during the first 6 months of zidovudine treatment. Eight patients were treated for an average of 11 weeks. There was a significant increase in T-CFC with zidovudine treatment (11.5 +/- 4.7% versus 29.8 +/- 6.9%, P less than 0.02 using a paired Student's t-test). There was a non-significant trend in the improvement of lymphocyte counts in these patients (872 +/- 117 versus 1102 +/- 204, NS). In vitro exposure of lymphocytes to zidovudine (200 mumol/l) resulted in modest suppression of T-CFC formation, suggesting that the effect of zidovudine treatment is indirect. Given that we have previously shown that inactivated HIV can inhibit T-CFC formation, we suggest that zidovudine treatment indirectly allows an increase in lymphocyte number by decreasing virus load, thereby permitting greater T-cell repopulation.

Acquired Immunodeficiency Syndrome↗
PubMed1989

2-Mercaptoethanol and n-acetylcysteine enhance T cell colony formation in AIDS and ARC.

One contributing factor to the loss of T cells in AIDS may be the impaired ability of T cell precursors to expand, as reflected in a decreased ability of patient cells to form T cell colonies in agar. We and others have noted such a defect in people with AIDS and ARC, and have found that suppressor cells and suppressive plasma contribute to decreased T-CFC formation. We report here that the reducing agents 2-mercaptoethanol (2-ME) and n-acetyl cysteine (NAC) can enhance colony formation in vitro. In part, 2-ME can reverse the defect in T cell colony-forming cells (T-CFC) formation by overcoming the effect of suppressor cells. In a group of 46 AIDS patients, T-CFC formation was initially 42 +/- 8% (mean +/- s.e.) that of control levels. 2-ME caused an increase of 401 +/- 76% in T-CFC formation which was significantly greater than the increase in control T-CFC formation; it also significantly enhanced T-CFC formation by cells from ARC patients. Suppressor cell activity from ten AIDS patients decreased from 58 +/- 21% to 12 +/- 10% when 2-ME was added. Similar data were obtained from 14 ARC patients. NAC, a related antioxidant with low toxicity, also enhanced T-CFC in cells of AIDS and ARC patients. Vitamin C generally did not increase T-CFC formation. The data suggest that certain antioxidants such as 2-ME and NAC may be useful in treatment protocols to enhance T cell numbers in patients with AIDS or ARC.

AIDS-Related Complex↗
PubMed1988

Characterization of plasma membrane shedding from murine melanoma cells.

Tumor cells release intact portions of their plasma membranes in the process of membrane fragment shedding. This released material has been shown to inhibit various synthetic functions of normal cells, which may play an important role in certain patho-physiological events occurring in advanced-stage cancer patients. Our studies on metastatic variants of the murine B16 melanoma, B16-F1 (low incidence of lung colonization) and B16-F10 (high incidence of lung colonization) indicate that the shed membrane fragment material is composed predominantly of vesicles, ranging in size from 20 to 100 nm in diameter. The release of membrane fragments represents a small percentage (approximately 16%) of the total shedding of plasma membrane components. Membrane fragments were shed at a higher rate from the highly "metastatic" (colonizing) B16-F10 cells than from poorly metastatic B16-F1 cells, resulting in a 2-fold greater accumulation of membrane fragment material by cultures of B16-F10 cells than by B16-F1 cultures during the 48-hr assay period. The study of various intracellu ar metabolic processes (protein and RNA synthesis, glycosylation, and generation of ATP) required for the shedding of membrane fragments indicated that the shedding event is only dependent on energy when inhibitors of the above processes are present for 2 hr. Treatment of cells with these inhibitors for 8 hr results in cessation of the shedding process, indicating both a limited pool of components to be shed and the requirement for further synthesis of the shed material. Glycoprotein components of the shed membrane fragments were analyzed by SDS-polyacrylamide gel electrophoresis. In addition to quantitative differences, 2 additional bands were present in fluorographs from SDS-PAGE gels from the B16-F10 membrane fragment material which were not present in fluorographs from B16-F1 fragments. The glycoprotein components of shed membrane fragments were shown to represent selected domains of the cell's plasma membranes, in that only certain plasma membrane glycoproteins are shed as part of membrane fragments. The glycoproteins released as non-particulate molecules into the extracellular environment failed to exhibit these quantitative and qualitative differences.

Adenosine Triphosphate↗
PubMed1986

Shedding of plasma membrane fragments. Neoplastic and developmental importance.

The phenomenon of shedding of cell surface macromolecules and their importance in the cancer process has been reviewed with particular emphasis on tumor membrane fragments. With cell activation (during growth or stimulation of normal cells), there is an increase in synthesis, processing, insertion, and eventual, intact release of certain membrane proteins, some of which are proteases. In cancer, these events occur spontaneously and without the temporal, physiological, or hormonal control apparent in normal cells. In a previous review (Black, 1980), many of the consequences of shedding tumor products were described, but the nature of the shed material was not clear. It now seems likely that some proteolytic, procoagulant, and immunosuppressive activities of shed material are contained within membrane particulate material (vesicles). Under normal conditions, shed membrane material (particularly proteolytic activity) may be necessary for cell movement and tissue remodeling which occur during embryogenesis. In cancer, shedding of plasma membrane fragments may be responsible for the key features of the malignant phenotype by the presence and release of proteolytic activity producing the separation of tumor cells from the primary site, invasion of the surrounding tissues by tumor cells, and formation of distinct metastases. Shed plasma membrane fragments may play a central role in tumor progression by enhancing the steps of the metastatic cascade, in particular by increasing tumor embolus formation (by enhanced fibrin deposition and platelet aggregation) and vascular permeability, as well as increasing basement membrane degradation. Shed membrane fragments (containing tumor antigens) either alone or complexed with antibody, may be responsible for blocking the cell-mediated immune reaction by the formation of "blocking factors" or by suppressing the formation of cytotoxic immune pathways. The suppression of immune response formation may be due to blocking of antigen presentation by macrophages (due to inhibition of Ia) or by the induction of Ts1 cells.

Animals↗
PubMed1986

Defective T-cell differentiation in acquired immune deficiency syndrome (AIDS).

A decline in T-cell lymphocyte number is the central characteristic of acquired immune deficiency syndrome (AIDS). The reason for the loss of these cells is not well understood. We investigated the hypothesis that defects in T-cell differentiation contributed to T-cell loss using an in vitro colony assay that measures T-cell precursor (CFU-T) frequency. The results indicate a substantial generalized decrease in CFU-T in people with AIDS (P less than 0.01), most of whom have Kaposi's sarcoma, and an occasionally severe decrease in CFU-T in people with ARC. Some of the cells from low colony formers suppressed colony formation by control cells. In addition, plasma from people with AIDS was less supportive of colony growth than control plasma. Decreased Ia expression on adherent mononuclear cells did not correlate with colony formation. A defect in T-cell repopulation can help explain the loss of T cells associated with AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1986

Elevation of circulating beta-endorphin levels with concomitant depression of immune parameters after traumatic injury.

Immunosuppression is frequently observed after traumatic injury, and is associated with the subsequent development of sepsis. Although a number of factors such as age, nutritional status, and the degree of injury have been related to the severity of the immunosuppression that occurs, the physiologic alterations leading to immunosuppression are not well defined. We hypothesized that changes in the endogenous opiate peptides, such as beta-endorphin, might contribute to changes in the immune system following injury. Levels of circulating beta-endorphin, responsiveness to the mitogen PHA, and the frequency of circulating T11, T4, and T8 cells were measured in trauma patients hospitalized in a surgical intensive care unit. beta-endorphin levels were elevated during the first 4 days after trauma (134.1 +/- 22.5 vs. 49.3 +/- 4.3 pg/ml, mean +/- S.E., patient vs. control; p less than 0.001). During the same time period patient PHA response (10,852 +/- 3,775 vs. 28,147 +/- 12,078; p less than 0.05), and the per cent of T4 positive (31.2 +/- 2.6 vs. 47.0 +/- 1.4; p less than 0.001) cells were lower than controls. These parameters were not significantly different from control values when measured at later times. Thus we conclude there is a temporal association of depressed immune parameters and elevated beta-endorphin levels after traumatic injury.

Endorphins↗
PubMed1985

Turnover and fate of I-Ak antigen on the murine macrophage cell surface.

The macrophage plasma membrane is a major site of the cell's activities, including phagocytosis, antibody-dependent cellular cytotoxicity, and antigen presentation. To present antigen, the expression by the macrophage of immune region-associated (Ia) antigen is required. The turnover and fate of this cell surface constituent was studied in macrophages cultured with lymphokine or recombinant interferon-gamma. Surface-labeled subregion I-Ak antigen was lost from the cell surface at a rapid rate, with a half-life of approximately 24 hours. However, the shedding of I-A antigen into the culture fluid was not detected. Therefore, the loss of I-A antigen from the macrophage surface is most likely by its degradation. Upon removal of lymphokine or interferon from macrophage cultures, I-A antigen expression declined, with an apparent half-life of 2 days.

Animals↗