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L Borish

Publications and source records attributed to L Borish.

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

Interleukin-10 regulation in normal subjects and patients with asthma.

Interleukin-10 or cytokine synthesis inhibitory factor has important antiinflammatory activities in immune diseases. We speculated that diminished IL-10 production in asthma would permit the unopposed synthesis of proinflammatory cytokines, contributing to the development and severity of asthma. Our data demonstrate constitutive secretion of IL-10 into bronchoalveolar lavage (BAL) fluid of normal, nonasthmatic subjects (130 +/- 61 pg/ml; n = 8). Asthmatic patients' BAL fluid was characterized by diminished concentrations of IL-10 (9 +/- 18 pg/ml; n = 8; p < 0.01 compared with that of normal subjects). By using the RNA-based polymerase chain reaction, we demonstrated that diminished IL-10 occurred as a result of inhibition of transcription. IL-10 transcription, but not protein, was observed at the time of the late asthmatic response. We speculate that the subsequent appearance of IL-10 protein could contribute to the resolution of the late asthmatic response. Similar to what was observed in the BAL fluid, peripheral blood mononuclear cells of patients with asthma demonstrated decreased spontaneous (0.01 +/- 0.01 ng/ml-asthmatic and 0.09 +/- 0.04 ng/ml-normal; p < 0.05) and stimulated (0.60 +/- 0.22 ng/ml-asthmatic and 1.69 +/- 0.49 ng/ml-normal; p < 0.05) IL-10 production compared with normal subjects. In support of the hypothesis that IL-10 mitigates the development of inflammation, we demonstrated that the addition of a neutralizing anti-IL-10 antibody to resting peripheral blood mononuclear cell cultures of normal subjects stimulated the spontaneous production of interferon-gamma (10.4 +/- 4.3 to 152.4 +/- 23.6 ng/ml; p < 0.01). Finally, we reasoned that corticosteroids might exert at least part of their antiinflammatory activity through the induction of IL-10 secretion. However, methylprednisolone inhibited the lipopolysaccharide-stimulated production of IL-10 (2.34 +/- 0.49 ng/ml IL-10 with lipopolysaccharide alone to 1.11 +/- 0.38 ng/ml in the additional presence of 10(-6) mol/L methylprednisolone; p < 0.05).

Adult↗
PubMed1996

Update on cytokines.

Explore the source record for details and available documents.

Allergy and Immunology↗
PubMed1996

Anti-inflammatory effects of theophylline: modulation of cytokine production.

BACKGROUND: The basis for the efficacy of theophylline in the treatment of asthma remains enigmatic. Although commonly classified as a bronchodilator, its ability to dilate smooth muscle is considered fairly poor and clinical responses are often independent of bronchodilation. Recent studies have suggested that immunomodulatory activities may contribute to the therapeutic benefit mediated by theophylline. OBJECTIVE: We performed these preliminary studies to determine whether theophylline modulates cytokine production by peripheral blood mononuclear cells. METHODS: Peripheral blood mononuclear cells were obtained from 24 asthmatic subjects and were left in a resting state or stimulated with either mitogens (phytohemagglutinin, lipopolysaccharide) or antigen (tetanus, cat) with or without the additional presence of theophylline (15 micrograms/dL). Supernatants were collected and evaluated for cytokine concentration by ELISA. RESULTS: Theophylline neither inhibited production of allergenic cytokines such as IL-4 nor modulated the repertoire of cytokines produced by TH cells. A statistically significant inhibition of spontaneous interferon-gamma synthesis was observed (24.5 +/- 8.6 to 13.4 +/- 4.2; P < .05). Theophylline did have anti-inflammatory effects on cytokines primarily produced by mononuclear phagocytic cells. Theophylline mediated a slight inhibition of TNF-alpha production (0.26 +/- 0.08 to 0.21 +/- 0.06; P < .05). Theophylline was also associated with a 2.8-fold increase in spontaneous production of the anti-inflammatory cytokine IL-10 (0.35 +/- 0.08 to 0.98 +/- 0.16 ng; P < .01). CONCLUSIONS: A relative absence of IL-10 characterizes the asthmatic airways and may contribute to the development and severity of allergic inflammation. Induction of IL-10 production by theophylline may therefore mitigate inflammation and contribute to the clinical efficacy of this class of medications.

Adjuvants, Immunologic↗
PubMed1994

The photocatalytic production of organic-free water for molecular biological and pharmaceutical applications.

The inability of conventional water-purification systems to meet the ultra-high purity needs of molecular biology and biopharmaceuticals reliably was attributed to their almost exclusive utilization of phase-transfer technologies. Water quality may unpredictably degrade when confronted by microorganism blooms or altered feed water characteristics. Photocatalytic point-of-use water-purification systems fed by deionized water were demonstrated to meet the most stringent water-purity needs of the molecular biologist. The reliability of the photocatalytic water-purification technology was attributed to its ability to destroy organic contaminants rather than just effect their phase transfer. Photocatalytically produced water was shown to be free of detectable microorganisms, DNA, endotoxins and RNAses. It is suitable for immunological studies involving tissue and other cell cultures because of its lack of detectable endotoxins. Because DNA was also undetectable, it is suitable for DNA and endotoxin zero-standards as well as pharmaceutical formulation. The photocatalytic water is a reliable substitute for diethyl pyrocarbonate-treated water used in RNA work, compatible with PCR and sufficiently free from other contaminants to be useful for most biochemical and enzymatic assays.

Base Sequence↗
PubMed1993

Activities of superoxide dismutases and NADPH oxidase in neutrophils obtained from asthmatic and normal donors.

PMN obtained from asthmatic subjects demonstrate a heightened respiratory burst with increased superoxide generation compared to normals. This enhanced superoxide anion generation could be secondary to increased activity of the respiratory burst NADPH oxidase or diminished metabolism of superoxide via superoxide dismutase (SOD). The two forms of SOD expressed in PMN, CuZnSOD expressed constitutively in the cytosol and inducible mitochondrial MnSOD, were investigated in asthmatics. Resting PMN from asthmatics (N = 9) contained significantly less MnSOD activity compared to controls (0.46 +/- 0.16 vs. 0.79 +/- 0.17 units/10(7) PMN, respectively; P = 0.0002). As several cytokines including interleukins (IL) -1, -4, and -6 as well as granulocyte macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF) enhance the PMN respiratory burst and are synthesized in the asthmatic lung, their effects on PMN MnSOD activity were assayed. In contrast to its effects on lymphocytes, both IL-1 and IL-6 significantly inhibited in a dose-dependent fashion the induction of MnSOD in PMN from normals (0.42 +/- 0.12 and 0.45 +/- 0.05 units/10(7) PMN, respectively, at 10 units/ml of each cytokine; P = 0.02 compared to resting cells) but failed to further modulate MnSOD production in asthmatic PMN. IL-4 and GM-CSF had no effect on MnSOD production, and TNF effects could not be studied because of its effects on cell viability. There were no differences in the activity of CuZnSOD (N = 9) or NADPH oxidase (N = 4) in the two groups. Inhibition of MnSOD activity in PMN secondary to cytokine exposure in the asthmatic lung could explain, at least in part, the increased generation of superoxide from PMN obtained from asthmatics. This would promote the presence and severity of inflammation in the asthmatic lung. These data further support a role for IL-1 and IL-6 in allergic inflammation.

Asthma↗
PubMed1993

Sézary syndrome with elevated serum IgE and hypereosinophilia: role of dysregulated cytokine production.

A 62-year-old man presented with a 4-year history of a pruritic erythematous rash. Initial workup was not diagnostic, and the rash was refractory to standard treatment. A complete blood cell count demonstrated a white cell count of 9100 cells/microliter with 61% polymorphonuclear neutrophils, 16% eosinophils, and 17% lymphocytes. A serum protein electrophoresis revealed an M spike identified as IgG kappa. His IgE level was 11,900 IU/ml. A bone marrow biopsy specimen demonstrated "atypical plasma cells" but was not diagnostic for myeloma. Peripheral blood smear was remarkable for highly convoluted lymphoid cells diagnostic for Sézary T cells. Consistent with this diagnosis, 89% of his peripheral blood CD2+ cells expressed CD4. The eosinophilia, elevated IgE level, and monoclonal gammopathy led to further investigations. Circulating adherent monocytes were 96% positive for presumed low-affinity IgE receptor expression as shown by surface IgE binding. In a 9-day lymphocyte coculture, the patient's T lymphocytes induced IgE production in vitro (1.25 ng/ml) by a normal donor's cultured B cells. A healthy donor's T cells failed to induce IgE production (0 ng/ml) in a similar culture system. In situ hybridization with an Sulfur-35-labeled cDNA probe revealed interleukin-4 mRNA expression by 84% and interleukin-2 mRNA expression by 62% of nonadherent peripheral blood mononuclear cells. Interleukin-5 mRNA was shown by reverse transcription and the polymerase chain reaction. These studies demonstrate a subject with Sézary T cell leukemia with hypereosinophilia and elevated IgE due to presumed enhanced interleukin-4 and interleukin-5 production by the Sézary T cells.

B-Lymphocytes↗
PubMed1992

Detection of alveolar macrophage-derived IL-1 beta in asthma. Inhibition with corticosteroids.

This study investigated alveolar macrophage function in asthma as assessed by the presence and source of the cytokine IL-1 beta. Bronchoalveolar lavage (BAL) fluid and cell pellets were obtained at 4 a.m. from a cohort of asthmatic subjects. Normal subjects were used as controls. Asthmatic BAL fluid contained 57.0 +/- 5.9 pg/ml of IL-1 beta as determined by ELISA. No IL-1 beta could be identified in the BAL fluid of the control group. This IL-1 represented synthesis by cells of the airway as assessed by the presence of IL-1 beta-specific mRNA transcripts in the BAL cell pellets. Inasmuch as IL-1 beta transcripts are known to be present for only a short time period after activation (approximately 0.5 to 16 h), the presence of transcripts represents recent cellular activation. Using the technique of in situ hybridization, IL-1 beta transcripts were found to be located exclusively within alveolar macrophages, and a mean of 40 +/- 14% of alveolar macrophage were activated at the time of the lavage. Corticosteroids are known to be efficacious in the treatment of asthma. Administration of a single 50-mg dose of prednisone at 3 p.m. resulted in diminished IL-1 beta protein concentration in the BAL fluid (28.3 +/- 5.7 pg/ml; p < 0.01 compared to baseline) and completely abrogated IL-1 beta mRNA expression. In summary, these studies demonstrate that IL-1 beta is synthesized within the airways by alveolar macrophage and suggest that IL-1 beta may be a mediator of asthma. Inhibition of IL-1 beta may be an additional mechanism for the efficacy of corticosteroids in the treatment of asthma.

Asthma↗
PubMed1992

Regulation of low affinity IgE receptor (CD23) expression on mononuclear phagocytes in normal and asthmatic subjects.

Mononuclear phagocytic cells contain low affinity receptors for IgE (Fc epsilon RII or CD23) which induce cellular activation in the presence of specific allergen. These studies were performed to quantify the expression by monocytes and alveolar macrophages of Fc epsilon RII in asthma and to determine biologic response modifiers that regulate Fc epsilon RII. Whereas 2.5 +/- 1.0% of the monocytes obtained from normal volunteers were Fc epsilon RII positive, this increased to 16.7 +/- 2.4% in asthma (p < 0.001). Stimulation of Fc epsilon RII expression on monocytes was shown to be an activity of IL-4 (24.5 +/- 5.9%), granulocyte-macrophage-CSF (28.1 +/- 5.2%), IFN-alpha (15.8 +/- 5.3%), IFN-gamma (10.4 +/- 3.7%), and macrophage-CSF (7.3 +/- 0.7%) but not of IL-2, IL-6, or TNF-alpha. Expression of Fc epsilon RII by these cytokines was associated with the induction of specific mRNA transcripts. Using Fc epsilon RII subtype specific primers in the polymerase chain reaction expansion of cDNA, cytokine-induced receptors were shown to be Fc epsilon RIIb. Alveolar macrophages from nonasthmatic subjects displayed minimal expression of Fc epsilon RII (3.2 +/- 1.2%); however, these receptors were present on 69.2 +/- 6.3% of asthmatic volunteers (p < 0.001). Induction of Fc epsilon RII appears specific for allergic asthma insofar as these receptors are also not expressed in subjects with interstitial lung disease (1.3 +/- 1.3%). As assessed by shift in mean fluorescence, instillation of allergen in the asthmatic's airway further up-regulated Fc epsilon RII on alveolar macrophages by 151 +/- 7%. Up-regulation of Fc epsilon RII in atopic individuals may therefore reflect allergen-induced exposure of mononuclear phagocytes to one or more of these cytokines. These studies suggest a mechanism by which an immunologic stimulus that leads to the production of these cytokines (e.g., allergen or viral infection) would contribute to the development or exacerbation of allergic disease.

Allergens↗
PubMed1992

Neutrophils from asthmatics exhibit diminished responsiveness to 2-chloroadenosine which is reversed by theophylline. Evidence for a cyclic-AMP-independent pathway on human neutrophils.

We have shown previously that neutrophils (PMNs) from patients with asthma have a more potent stimulated respiratory burst than normals and that their respiratory burst is significantly less suppressed with exposure to 2-chloroadenosine (2-CADO). The present studies investigated the basis of this defect in responsiveness to 2-CADO. PMNs obtained from asthmatics either not on theophylline (minus theophylline) or taking theophylline (plus theophylline) generated significantly more superoxide in response to 2 x 10(-8) M FMLP (2.08 +/- 0.36 nmol/5 x 10(5) PMNs (minus theophylline) (P less than 0.01 compared to controls) vs. 2.16 +/- 0.44 (plus theophylline) (P less than 0.01) as compared to controls (1.05 +/- 0.17 nmol). In the presence of FMLP (2 x 10(-8) M), PMNs from the minus theophylline cohort had less 2-CADO (10(-6) M)-mediated suppression of superoxide generation as compared to controls (38.3 +/- 3.8% vs. 67.1 +/- 3.8%; (P less than 0.001). The plus theophylline group exhibited suppression values similar to controls (64.5 +/- 7.2%). Theophylline, in the presence of a physiological concentration of 2-CADO (0.1 microM) accentuated the suppression of the respiratory burst in normals (74.1 +/- 5.9%, 80.1 +/- 4.9% (P less than 0.02) and 84.7 +/- 3.8% (P less than 0.02) at 0, 10, and 100 microM, respectively). PMNs from asthmatics not taking theophylline demonstrated suppression values of 46.2 +/- 6%, 53.8 +/- 6.6% (P = NS), and 63.2 +/- 7.1% (P less than 0.01), respectively. Resting PMNs from normal controls generated 0.97 +/- 0.20 pmol cAMP/10(7) cells compared to 2.83 +/- 0.75 pmol in the presence of 0.1 microM 2-CADO. The combination of 2-CADO and theophylline (10-100 microM) produced cAMP concentrations not significantly different from that observed with 2-CADO alone. These findings support the existence of a novel cAMP-independent adenosine receptor in PMNs. The specific binding of 10(-8)M 3H-labeled 2-CADO (in delta cpm) was 10,358 +/- 1502 (P less than 0.001 compared to controls), 5468 +/- 843 (NS compared to controls), and 3751 +/- 477 in the plus theophylline group, minus theophylline group, and controls, respectively. Such up-regulation of specific binding may represent the effects of theophylline as shown by the specific binding of [3H]2-CADO in PMNs from normal controls exposed to 10 microM theophylline for 30 min (6013 +/- 969) compared to unexposed PMNs (3768 +/- 656; P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)

2-Chloroadenosine↗
PubMed1992

Transthyretin is an inhibitor of monocyte and endothelial cell interleukin-1 production.

Human serum was found to contain an inhibitor of constitutive interleukin-1 (IL-1) production by human umbilical vein endothelial cells (ECs). Purification of the serum activity by anion exchange chromatography, molecular sieve HPLC, and hydroxyl apatite chromatography yielded material 82% pure with a molecular weight of 17 kDa by SDS-PAGE. Amino acid sequencing revealed the purified inhibitor to be transthyretin (TTR), a liver-derived protein. There was a 42.6% reduction in the production of spontaneous IL-1 activity in EC supernatants after coculture with 10 micrograms/ml TTR. TTR was subsequently found by ELISA to inhibit LPS-stimulated IL-1 production by cells of the human monocytic leukemia line THP-1 by 47.1 +/- 9.4%, whereas a less striking but still significant inhibition of monocyte-derived IL-1 beta production was also observed. Inhibition of IL-1 secretion correlated with increased IL-1 mRNA synthesis in both THP-1 cells and monocytes. Furthermore, TTR was associated with increased intracellular concentrations of IL-1 beta. These data suggest that TTR functions by inhibiting processing of newly synthesized peptide for secretion. This novel inhibitory effect of TTR on the production of IL-1 activity suggests a previously unrecognized endogenous antiinflammatory mediator.

Amino Acid Sequence↗
PubMed1992

Inflammation and the allergic response.

The atopic diseases--allergic rhinitis, asthma, and atopic dermatitis--are chronic inflammatory diseases characterized by an exacerbating and remitting course and can only rarely be associated causally with allergen exposure. The challenge to ascribe an allergic basis to these diseases is derived from the apparent inability to reconcile these chronic inflammatory features with a process thought to be initiated by the rapid release of mediators after the interaction of allergen with IgE-coated mast cells. The traditional understanding has been that mast cell activation results in the release of a series of preformed and rapidly synthesized substances that mediate the immediate onset of vasodilatation, vascular leakage, smooth muscle contraction, and irritant nerve receptor stimulation. These mediators, however, are rapidly degraded and are not thought to be associated with a significant inflammatory component. Recent studies, however, have established that the interaction of allergen with the immune system is, in fact, far more complex (Fig. 4). In addition to mast cell activation, allergen can interact with and activate T-lymphocytes and mononuclear phagocytic cells, leading to the secretion of cytokines and other inflammatory substances. Furthermore, the interaction of allergen with the mast cell may be far more complex, with the potential to stimulate the delayed release of newly synthesized cytokines. The interaction of allergen with the immune system also promotes the secondary release of inflammatory neuropeptides. Thus, the known spectrum of mediators released after allergen exposure has vastly been expanded. These include numerous still uncharacterized chemotactic and activating peptides; eicosanoids such as 5-HETE, 12-HETE, and leukotriene B4; platelet-activating factor; several proteases; neuropeptides and, most importantly, the cytokines. These mediators recruit and activate neutrophils, monocytes, basophils, and eosinophils, attract additional lymphocytes and mononuclear phagocytic cells, and induce mast cell proliferation with further mast cell degranulation. A vicious cycle subsequently develops, with further inflammation and tissue destruction. Thus, the interaction of allergen with the immune system has become a complex cascade capable of producing the chronic inflammatory changes characteristic of allergic diseases.

Cytokines↗
PubMed1992

Anti-inflammatory effects of nedocromil sodium: inhibition of alveolar macrophage function.

The IgE-dependent activation of mononuclear phagocytic cells through their capacity to express low affinity IgE receptors (Fc epsilon RII) has been proposed as a mechanism for the development of airways inflammation in allergic asthma. This Fc epsilon RII expression leads to the IgE-dependent production of the potent pro-inflammatory cytokines IL-1 beta and TNF-alpha. Expression by monocytes of Fc epsilon RII is regulated by several cytokines including interleukin-4, gamma- and alpha-interferons, and granulocyte-macrophage and macrophage colony stimulating factors. An anti-inflammatory effect of nedocromil on monocytes has been proposed as a possible mechanism for its anti-asthma activity. We therefore investigated the capacity of nedocromil to modulate mononuclear phagocyte Fc epsilon RII expression and cytokine production. We used an anti-Fc epsilon RII antibody and flow cytometric analysis to assess the capacity of nedocromil to modulate cytokine-induced Fc epsilon RII expression in normals and asthmatics. Monocytes, THP-1 monocyte leukaemia cells, and alveolar macrophages were exposed to varying concentrations of these cytokines for 48 hr at 37 degrees C with or without the additional presence of nedocromil (1-10 microM) and the per cent of monocytes expressing Fc epsilon RII was determined. No changes in Fc epsilon RII expression were observed. Subsequently, we investigated the capacity of nedocromil to affect the capacity of IgE plus anti-IgE complexes, allergen, and LPS (16 hr/37 degrees C) to stimulate IL-1 beta and IL-6 production. No changes were observed when nedocromil was applied concomitant with the stimulus.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1992

Physiological studies with human leukocyte inhibitory factor.

LIF has been shown to be a potentially important activator of neutrophil function. By means of its dose-dependent dichotomous effects on chemotaxis, LIF can be predicted to both enhance the potency of chemotactic stimuli and promote the passive accumulation of PMN at inflammatory loci. Furthermore, LIF's stimulatory effects on both PMN- and endothelial cell-mediated adherence will promote the migration of neutrophils from the circulation to the inflammatory site. We have demonstrated LIF stimulation of fMLP, CR1, and CR3 expression and function, as well a stimulated Fc gamma RIII function. Through both receptor-dependent and -independent effects. LIF produces increased target cell attachment, phagocytosis, respiratory burst activity, and degranulation. Together, these effects result in a significant increase in killing of both phagocytosed targets and extracellular targets.

Chemotaxis, Leukocyte↗
PubMed1991

IgE-dependent cytokine production by human peripheral blood mononuclear phagocytes.

These studies demonstrate the IgE-dependent production of IL-1 beta and TNF-alpha by circulating blood monocytes. IL-1 beta production was demonstrated biologically as the stimulation of proliferation of the cloned IL-1-dependent murine T cell line D10.G4.1 in the presence of a submitogenic concentration of PHA. In a representative experiment, 3H-thymidine uptake increased from 57826 cpm in the presence of supernatants obtained from unstimulated cells to 200774 cpm with supernatants from monocytes stimulated by IgE/alpha IgE immune complexes. By ELISA, IgE complexes increased IL-1 beta production from 0.54 +/- 0.06 ng (per 10(6) monocytes) to 2.60 +/- 0.62 ng (p less than 0.01; mean of eight experiments) and TNF-alpha production from 0.17 +/- 0.10 ng to 3.00 +/- 0.54 ng (p less than 0.01; mean of four experiments). No IL-1 alpha secretion was observed. RNA hybridization analysis demonstrated that IL-1 beta production represented de novo synthesis of the cytokine. Stimulated RNA production was observed after a minimal 1/2-h incubation and was maximal at 2 h. The IgE-dependent secretion of these pro-inflammatory cytokines by mononuclear phagocytic cells may contribute to the inflammation characteristic of allergic responses.

Antigens, CD↗