Pharmacokinetics and immunomodulatory properties of intravenously administered recombinant human interleukin-10 in healthy volunteers

Normal volunteers received single doses of recombinant human interleukin-10 (rhIL-10; n = 6 per group) or placebo (n = 3 per group) by intravenous injection to characterize pharmacokinetics, tolerability, and immunomodulatory effects. Dosages were 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 25.0, 50.0, and 100.0 micrograms/kg. Dose-related adverse effects consisted of a mild-to-moderate flu-like syndrome characterized by fever with chills, headache, and myalgias at the highest dose. The mean terminal phase t1/2 ranged from 2.3 +/- 0.5 to 3.7 +/- 0.8 hours. Dose-related effects of rhIL-10 included transient increases of circulating neutrophils and monocytes and decreases of lymphocytes. rhIL-10 markedly suppressed, in a time- and dose-dependent manner, the synthesis of the inflammatory cytokines IL-1 beta and tumor necrosis factor alpha by whole blood stimulated ex vivo with bacterial lipopolysaccharide. Circulating numbers of CD14+/HLA-DR+ cells at 24 hours after the dose were increased in a dose-dependent manner. Effects on expression of HLA-DR by CD14+ cells were variable. There was no apparent effect on HLA-DR expression by CD20+ cells. The immunomodulatory effects of rhIL-10 merit further clinical investigation.

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The Host Antimicrobial Protein Calgranulin C Participates in the Control ofCampylobacter jejuniGrowth via Zinc Sequestration

Infection and Immunity ◽

10.1128/iai.00234-18 ◽

2018 ◽

Vol 86 (6) ◽

Cited By ~ 6

Author(s):

Janette M. Shank ◽

Brittni R. Kelley ◽

Joseph W. Jackson ◽

Jessica L. Tweedie ◽

Dana Franklin ◽

...

Keyword(s):

Campylobacter Jejuni ◽

Serum Levels ◽

Interleukin 10 ◽

Poultry Meat ◽

Antimicrobial Protein ◽

Dependent Manner ◽

Necrosis Factor Alpha ◽

Content Type ◽

Full Resolution ◽

Factor Alpha

ABSTRACTCampylobacter jejuniis a leading cause of bacterially derived gastroenteritis worldwide.Campylobacteris most commonly acquired through the consumption of undercooked poultry meat or through drinking contaminated water. Following ingestion,Campylobacteradheres to the intestinal epithelium and mucus layer, causing toxin-mediated inflammation and inhibition of fluid reabsorption. Currently, the human response to infection is relatively unknown, and animal hosts that model these responses are rare. As such, we examined patient fecal samples for the accumulation of the neutrophil protein calgranulin C during infection withCampylobacter jejuni. In response to infection, calgranulin C was significantly increased in the feces of humans. To determine whether calgranulin C accumulation occurs in an animal model, we examined disease in ferrets. Ferrets were effectively infected byC. jejuni, with peak fecal loads observed at day 3 postinfection and full resolution by day 12. Serum levels of interleukin-10 (IL-10) and tumor necrosis factor alpha (TNF-α) significantly increased in response to infection, which resulted in leukocyte trafficking to the colon. As a result, calgranulin C increased in the feces of ferrets at the time whenC. jejuniloads decreased. Further, the addition of purified calgranulin C toC. jejunicultures was found to inhibit growth in a zinc-dependent manner. These results suggest that upon infection withC. jejuni, leukocytes trafficked to the intestine release calgranulin C as a mechanism for inhibitingC. jejunigrowth.

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Bikunin Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor Alpha Induction in Macrophages

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.11.6.1140-1147.2004 ◽

2004 ◽

Vol 11 (6) ◽

pp. 1140-1147 ◽

Cited By ~ 17

Author(s):

Hidenori Matsuzaki ◽

Hiroshi Kobayashi ◽

Tatsuo Yagyu ◽

Kiyoshi Wakahara ◽

Toshiharu Kondo ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Mitogen Activated Protein Kinase ◽

Dependent Manner ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Factor Alpha ◽

Dose Dependent ◽

Necrosis Factor

ABSTRACT Bikunin, a Kunitz-type protease inhibitor, exhibits anti-inflammatory activity in protection against cancer and inflammation. To investigate the molecular mechanism of this inhibition, we analyzed the effect of bikunin on tumor necrosis factor alpha (TNF-α) production in human peripheral mononuclear cells stimulated by lipopolysaccharide (LPS), an inflammatory inducer. Here, we show the following results. (i) LPS induced TNF-α expression in time- and dose-dependent manners through phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase pathways. (ii) Bikunin inhibits LPS-induced up-regulation of TNF-α protein expression in a dose-dependent manner, reaching 60% inhibition at the highest doses of bikunin tested (5.0 μM). (iii) Inhibition by bikunin of TNF-α induction correlates with the suppressive capacity of ERK1/2, JNK, and p38 signaling pathways, implicating repressions of at least three different signals in the inhibition. (iv) Bikunin blocks the induction of TNF-α target molecules interleukin-1β (IL-1β) and IL-6 proteins. (v) Bikunin is functional in vivo, and this glycoprotein blocks systemic TNF-α release in mice challenged with LPS. (vi) Finally, bikunin can prevent LPS-induced lethality. In conclusion, bikunin significantly inhibits LPS-induced TNF-α production, suggesting a mechanism of anti-inflammation by bikunin through control of cytokine induction during inflammation. Bikunin might be a candidate for the treatment of inflammation, including septic shock.

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Factors Associated with Severe Granulomatous Pneumonia in Mycobacterium tuberculosis-Infected Mice Vaccinated Therapeutically with hsp65 DNA

Infection and Immunity ◽

10.1128/iai.73.8.5189-5193.2005 ◽

2005 ◽

Vol 73 (8) ◽

pp. 5189-5193 ◽

Cited By ~ 26

Author(s):

Jennifer L. Taylor ◽

Diane J. Ordway ◽

JoLynn Troudt ◽

Mercedes Gonzalez-Juarrero ◽

Randall J. Basaraba ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Ex Vivo ◽

Interleukin 10 ◽

Lung Pathology ◽

Necrosis Factor Alpha ◽

Cd8 Cells ◽

Factor Alpha ◽

Cell Gene ◽

Granulomatous Pneumonia ◽

Necrosis Factor

ABSTRACT Resistant C57BL/6 mice infected in the lungs with Mycobacterium tuberculosis and then therapeutically vaccinated with Mycobacterium leprae-derived hsp65 DNA develop severe granulomatous pneumonia and tissue damage. Analysis of cells accumulating in the lungs of these animals revealed substantial increases in T cells secreting tumor necrosis factor alpha and CD8 cells staining positive for granzyme B. Stimulation of lung cells ex vivo revealed very high levels of interleukin-10, some of which was produced by B-1 B cells. This was probably an anti-inflammatory response, since lung pathology was dramatically worsened in B-cell gene-disrupted mice.

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Superoxide responses of endothelial cells to C5a and TNF-alpha: divergent signal transduction pathways

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1992.263.1.l51 ◽

1992 ◽

Vol 263 (1) ◽

pp. L51-L59 ◽

Cited By ~ 14

Author(s):

H. S. Murphy ◽

J. A. Shayman ◽

G. O. Till ◽

M. Mahrougui ◽

C. B. Owens ◽

...

Keyword(s):

Signal Transduction ◽

Endothelial Cells ◽

Tnf Alpha ◽

Dependent Manner ◽

Necrosis Factor Alpha ◽

Cell Monolayers ◽

Kinase C ◽

Factor Alpha ◽

Dose Dependent ◽

Necrosis Factor

There is increasing evidence that endothelial cells respond to a variety of mediators. In the current studies rat pulmonary artery endothelial cells (RPAEC) responded to human recombinant C5a and tumor necrosis factor-alpha (TNF-alpha) with the generation of superoxide (O2-). RPAEC responsiveness was dependent on whether cells had been obtained from confluent or subconfluent cell monolayers. RPAEC responded to C5a and TNF-alpha in a dose-dependent manner, with increases in intracellular Ca2+ (Cai2+), formation of D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], and generation of O2-. Optimal O2- responses occurred in cells that had been pretreated with the inhibitor of superoxide dismutase (SOD), diethyldithiocarbamate, and O2- responses were allopurinol insensitive. Pertussis toxin pretreatment abolished the ability of C5a to cause increases in Ins(1,4,5)P3 and Cai2+ and formation of O2- but did not inhibit the changes in Cai2+ and formation of O2- after addition of TNF-alpha. The O2- response to C5a but not to TNF-alpha was abolished by pretreatment with the inhibitor of protein kinase C, staurosporine. These data indicate that signal transduction events in response to C5a and TNF-alpha were fundamentally different.

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Inhibition of Escherichia coli-Induced Meningitis by Carboxyfullerence

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.9.2273 ◽

1999 ◽

Vol 43 (9) ◽

pp. 2273-2277 ◽

Cited By ~ 67

Author(s):

Nina Tsao ◽

Puthuparampil P. Kanakamma ◽

Tien-Yau Luh ◽

Chen-Kung Chou ◽

Huan-Yao Lei

Keyword(s):

Escherichia Coli ◽

Water Soluble ◽

Dependent Manner ◽

Neutrophilic Infiltration ◽

Necrosis Factor Alpha ◽

E Coli ◽

Brain Barrier Permeability ◽

Factor Alpha ◽

Dose Dependent ◽

Necrosis Factor

ABSTRACT The effect of a water-soluble malonic acid derivative of carboxyfullerence (C60) against Escherichia coli-induced meningitis was tested. C60 can protect the mice from E. coli-induced death in a dose-dependent manner. C60 administered intraperitoneally as late as 9 h after E. coliinjection was still protective. The C60-treated mice had less tumor necrosis factor alpha and interleukin-1β production by staining of brain tissue compared to the levels of production for nontreated mice. The E. coli-induced increases in blood-brain barrier permeability and inflammatory neutrophilic infiltration were also inhibited. These data suggest that C60 is a potentially therapeutic agent for bacterial meningitis.

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Pretreatment of Mice with Clindamycin Improves Survival of Endotoxic Shock by Modulating the Release of Inflammatory Cytokines

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.9.2638-2642.2001 ◽

2001 ◽

Vol 45 (9) ◽

pp. 2638-2642 ◽

Cited By ~ 29

Author(s):

Norio Hirata ◽

Kazufumi Hiramatsu ◽

Kenji Kishi ◽

Tohru Yamasaki ◽

Tomoku Ichimiya ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Interleukin 1 ◽

Endotoxic Shock ◽

Dependent Manner ◽

Necrosis Factor Alpha ◽

Inflammatory Cytokine Production ◽

E Coli ◽

Factor Alpha ◽

Dose Dependent ◽

Necrosis Factor

ABSTRACT Suppression of endotoxin release and subsequent production of inflammatory cytokines is crucial in the treatment of septic shock. We investigated the effect of clindamycin (CLI) on endotoxic shock induced in mice by Escherichia coli lipopolysaccharide (LPS). Mice were treated with CLI (160 to 600 mg/kg) or saline and then injected with E. coli LPS and d-(+)-galactosamine intraperitoneally 0.5 h after CLI administration. Pretreatment with CLI significantly improved survival in a dose-dependent manner (CLI, at 160, 300, and 440 mg/kg) and significantly lowered the peak concentrations of tumor necrosis factor alpha and interleukin-1β (IL-1β) in serum. However, the peak concentrations of IL-6 in the sera of CLI-treated mice were higher than in control mice. Our findings suggest that CLI alters LPS-induced inflammatory cytokine production and suppresses endotoxin-induced mortality in this murine model.

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Enterotoxin-Based Mucosal Adjuvants Alter Antigen Trafficking and Induce Inflammatory Responses in the Nasal Tract

Infection and Immunity ◽

10.1128/iai.73.10.6892-6902.2005 ◽

2005 ◽

Vol 73 (10) ◽

pp. 6892-6902 ◽

Cited By ~ 62

Author(s):

Frederik W. van Ginkel ◽

Raymond J. Jackson ◽

Naoto Yoshino ◽

Yukari Hagiwara ◽

Daniel J. Metzger ◽

...

Keyword(s):

Inflammatory Responses ◽

Vaccine Antigen ◽

Dependent Manner ◽

Necrosis Factor Alpha ◽

B Subunit ◽

Antigen Trafficking ◽

Factor Alpha ◽

Adp Ribosyltransferase ◽

Dose Dependent

ABSTRACT The safety of nasal vaccines containing enterotoxin-based mucosal adjuvants has not been studied in detail. Previous studies have indicated that native cholera toxin (nCT) can alter antigen trafficking when applied nasally. In this study, we determined the enterotoxin-based variables that alter antigen trafficking. To measure the influence of enterotoxin-based mucosal adjuvants on antigen trafficking in the nasal tract, native and mutant enterotoxins were coadministered with radiolabeled tetanus toxoid (TT). The nCT and heat-labile enterotoxin type 1 (LTh-1) redirected TT into the olfactory neuroepithelium (ON/E). Antigen redirection occurred mainly across the nasal epithelium without subsequent transport along olfactory neurons into the olfactory bulbs (OB). Thus, no significant accumulation of the vaccine antigen TT was observed in the OB when coadministered with nCT. In contrast, neither mutant CT nor mutant LTh-1, which lack ADP-ribosyltransferase activity, redirected TT antigen into the ON/E. Thus, ADP-ribosyltransferase activity was essential for antigen trafficking across the olfactory epithelium. Accumulation of TT in the ON/E was also due to B-subunit binding to GM1 gangliosides, as was demonstrated (i) by redirection of TT by LTh-1 in a dose-dependent manner, (ii) by ganglioside inhibition of the antigen redirection by LTh-1 and nCT, and (iii) by the use of LT-IIb, a toxin that binds to gangliosides other than GM1. Redirection of TT into the ON/E coincided with elevated production of interleukin 6 (IL-6) but not IL-1β or tumor necrosis factor alpha in the nasal mucosa. Thus, redirection of TT is dependent on ADP-ribosyltransferase activity and GM1 binding and is associated with production of the inflammatory cytokine IL-6.

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Sedative and Immunosuppressive Effects of Dexmedetomidine in Transplantation

Pharmaceuticals ◽

10.3390/ph14080825 ◽

2021 ◽

Vol 14 (8) ◽

pp. 825

Author(s):

Chen-Fang Lee ◽

Chih-Hsien Cheng ◽

Hao-Chien Hung ◽

Jin-Chiao Lee ◽

Yu-Chiao Wang ◽

...

Keyword(s):

Treated Group ◽

Dependent Manner ◽

Post Transplantation ◽

Necrosis Factor Alpha ◽

Donor Liver Transplantation ◽

Tnf Α ◽

Factor Alpha ◽

Light Sedation ◽

Dose Dependent ◽

Adrenergic Receptor Agonist

Dexmedetomidine, an α2-adrenergic receptor agonist, is used as an anti-anxiety medication. It exerts a cholinergic effect, thereby reducing the release of tumor necrosis factor alpha (TNF-α). We hypothesized that the use of dexmedetomidine as a sedative agent in transplantation would also protect allografts. We examined our patients who underwent living donor liver transplantation. Subsequently, we generated a series of mouse models to investigate the effect of dexmedetomidine on sedation-based tolerance post transplantation. A total of 49 liver recipients were enrolled in this study, of which 23 (47%) were administered dexmedetomidine through 24 h infusion on postoperative day 1. A trend toward the improvement of hepatocyte injury along with better liver function was observed in the dexmedetomidine-treated group during the first postoperative week. In animal models, dexmedetomidine inhibited the proliferation of CD4+ and CD8+ T cells and TNF-α production in a dose-dependent manner. We used dexmedetomidine to treat skin-transplanted mice and observed a significantly prolonged graft survival in mice that were administered a higher dose of dexmedetomidine. Our results revealed that dexmedetomidine exerts a dual effect of sedation and immunosuppression. This light-sedation approach will not only make patients calmer in the intensive care unit but also protect allografts from injury.

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Influence of Mycobacterium avium subsp. paratuberculosis on Colitis Development and Specific Immune Responses during Disease

Infection and Immunity ◽

10.1128/iai.01770-06 ◽

2007 ◽

Vol 75 (8) ◽

pp. 3722-3728 ◽

Cited By ~ 17

Author(s):

Udai P. Singh ◽

Shailesh Singh ◽

Rajesh Singh ◽

Russell K. Karls ◽

Frederick D. Quinn ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mycobacterium Avium ◽

Ex Vivo ◽

Cell Receptor ◽

Interleukin 10 ◽

Necrosis Factor Alpha ◽

Bowel Diseases ◽

Factor Alpha ◽

Mycobacterium Avium Subsp Paratuberculosis

ABSTRACT The granulomatous and intramural inflammation observed in cases of inflammatory bowel diseases (IBD) and veterinary Johne's disease suggests that Mycobacterium avium subsp. paratuberculosis is a causative agent. However, an incomplete understanding of the immunological steps responsible for the pathologies of IBD makes this conclusion uncertain. Sera from interleukin-10-deficient (IL-10−/−) mice with spontaneous colitis displayed significantly higher M. avium subsp. paratuberculosis-specific immunoglobulin G2a antibody responses than did sera from similar mice without disease. Pathogen-free IL-10−/− mice received control vehicle or the vehicle containing heat-killed or live M. avium subsp. paratuberculosis. Mucosal CD4+ T cells from the mice that developed colitis proliferated and secreted higher levels of gamma interferon and tumor necrosis factor alpha after ex vivo stimulation with a Vβ11+ T-cell receptor-restricted peptide from the MPT59 antigen (Ag85B) than those secreted from cells from mice before the onset of colitis. The data from this study provide important information regarding the mechanisms of colitis in IL-10−/− mice, which are driven in part by Ag85B-specific T cells. The data suggest a plausible mechanism of Ag-specific T-cell responses in colitis driven by potent Ags conserved in Mycobacterium species.

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Effect of Contaminating Red Blood Cells on OKT3-Mediated Polyclonal Activation of Peripheral Blood Mononuclear Cells

Clinical and Vaccine Immunology ◽

10.1128/cdli.9.3.708-712.2002 ◽

2002 ◽

Vol 9 (3) ◽

pp. 708-712 ◽

Cited By ~ 1

Author(s):

Samuel Song ◽

Joseph Goodwin ◽

Jenny Zhang ◽

Bruce Babbitt ◽

Janet L. Lathey

Keyword(s):

Red Blood Cells ◽

Peripheral Blood ◽

Blood Cells ◽

Mononuclear Cells ◽

Dependent Manner ◽

Peripheral Blood Mononuclear ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Dose Dependent ◽

Necrosis Factor

ABSTRACT Erythrocytes are typically present as impurities in the majority of peripheral blood mononuclear cell (PBMC) preparations. This study was undertaken to investigate the effects of contaminating red blood cells (RBC) on the ability of OKT3 to activate CD4+ and CD8+ T cells. Surprisingly, the levels of gamma interferon, tumor necrosis factor alpha, and interleukin-1β (IL-1β) produced by PBMC upon stimulation by OKT3 were increased (P < 0.05) in a dose-dependent manner when increasing amounts of autologous RBC (RBC-to-PBMC ratios of 2:1, 10:1, and 50:1) were spiked into PBMC preparations. The OKT3-driven induction of the IL-2 receptor (CD25) and the proliferation of T lymphocytes in response to phorbol myristate acetate were not affected by the addition of RBC.

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