A non-linear mixed effect model for innate immune response: In vivo kinetics of endotoxin and its induction of the cytokines tumor necrosis factor alpha and interleukin-6

The endothelial molecule E-selectin binds most leukocyte subsets in vitro. Yet its role in regulating the very different kinetics of inflammatory infiltration of different leukocyte subsets in vivo is unclear. The kinetics of E-selectin upregulation and polymorphonuclear leukocyte (PMN) and blood lymphocyte (PBL) localization in inflammation induced by interleukin-1 alpha (IL-1 alpha), tumor necrosis factor-alpha (TNF-alpha), phytohemagglutinin (PHA), and phorbol myristate acetate (PMA) were investigated in a well-established inbred pig trafficking model. They differed markedly both for these three labeled indicators of inflammation and in each of the four inflammatory processes. In each, E-selectin upregulation correlated with early PMN entry and later with PBL infiltration but was more protracted than both. The importance of E-selectin was confirmed by marked inhibition of PMN and PBL entry (up to > 60%) by F(ab')2 anti-E-selectin. Involvement of other molecules was illustrated by similar or greater inhibition with anti-CD18 F(ab')2. We conclude that, like CD18, E-selectin is necessary for most PMN and PBL infiltration but alone is insufficient, consistent with the involvement of several alternative multistep molecular mechanisms in this entry.

Download Full-text

P3442 In vivo inhibition of tumour necrosis factor-alpha reverses mitochondrial dysfunction in pacing-induced cardiomyopathy: Insights into role of cytokines and heart failure progression

European Heart Journal ◽

10.1016/s0195-668x(03)96068-4 ◽

2003 ◽

Vol 24 (5) ◽

pp. 665

Author(s):

J MARINGARCIA

Keyword(s):

Heart Failure ◽

Mitochondrial Dysfunction ◽

Tumour Necrosis ◽

Tumour Necrosis Factor Alpha ◽

Necrosis Factor Alpha ◽

Heart Failure Progression ◽

Factor Alpha ◽

Necrosis Factor

Download Full-text

‘Educated’ Osteoblasts Reduce Osteoclastogenesis in a Bone-Tumor Mimetic Microenvironment

Cancers ◽

10.3390/cancers13020263 ◽

2021 ◽

Vol 13 (2) ◽

pp. 263

Author(s):

Alexus D. Kolb ◽

Jinlu Dai ◽

Evan T. Keller ◽

Karen M. Bussard

Keyword(s):

Bone Resorption ◽

Bone Tumor ◽

Bone Matrix ◽

Necrosis Factor Alpha ◽

Tumor Bearing ◽

Receptor Activator ◽

Factor Alpha ◽

Osteoclast Resorption ◽

Necrosis Factor

Breast cancer (BC) metastases to bone disrupt the balance between osteoblasts and osteoclasts, leading to excessive bone resorption. We identified a novel subpopulation of osteoblasts with tumor-inhibitory properties, called educated osteoblasts (EOs). Here we sought to examine the effect of EOs on osteoclastogenesis during tumor progression. We hypothesized that EOs affect osteoclast development in the bone-tumor niche, leading to suppressed pre-osteoclast fusion and bone resorption. Conditioned media (CM) was analyzed for protein expression of osteoclast factors receptor activator of nuclear factor kappa-β ligand (RANKL), osteoprotegerin (OPG), and tumor necrosis factor alpha (TNFα) via ELISA. EOs were co-cultured with pre-osteoclasts on a bone mimetic matrix to assess osteoclast resorption. Pre-osteoclasts were tri-cultured with EOs plus metastatic BC cells and assessed for tartrate-resistance acid phosphatase (TRAP)-positive, multinucleated (≥3 nuclei), mature osteoclasts. Tumor-bearing murine tibias were stained for TRAP to determine osteoclast number in-vivo. EO CM expressed reduced amounts of soluble TNFα and OPG compared to naïve osteoblast CM. Osteoclasts formed in the presence of EOs were smaller and less in number. Upon co-culture on a mimetic bone matrix, a 50% reduction in the number of TRAP-positive osteoclasts formed in the presence of EOs was observed. The tibia of mice inoculated with BC cells had less osteoclasts per bone surface in bones with increased numbers of EO cells. These data suggest EOs reduce osteoclastogenesis and bone resorption. The data imply EOs provide a protective effect against bone resorption in bone metastatic BC.

Download Full-text

Human Immunodeficiency Virus Infection Alters Tumor Necrosis Factor Alpha Production via Toll-Like Receptor-Dependent Pathways in Alveolar Macrophages and U1 Cells

Journal of Virology ◽

10.1128/jvi.00362-08 ◽

2008 ◽

Vol 82 (16) ◽

pp. 7790-7798 ◽

Cited By ~ 26

Author(s):

Marlynne Q. Nicol ◽

Jean-Marie Mathys ◽

Albertina Pereira ◽

Kevin Ollington ◽

Michael H. Ieong ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Innate Immune ◽

Hiv Positive ◽

Toll Like Receptor ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Immunodeficiency Virus ◽

Factor Alpha ◽

Necrosis Factor

ABSTRACT Human immunodeficiency virus (HIV)-positive persons are predisposed to pulmonary infections, even after receiving effective highly active antiretroviral therapy. The reasons for this are unclear but may involve changes in innate immune function. HIV type 1 infection of macrophages impairs effector functions, including cytokine production. We observed decreased constitutive tumor necrosis factor alpha (TNF-α) concentrations and increased soluble tumor necrosis factor receptor type II (sTNFRII) in bronchoalveolar lavage fluid samples from HIV-positive subjects compared to healthy controls. Moreover, net proinflammatory TNF-α activity, as measured by the TNF-α/sTNFRII ratio, decreased as HIV-related disease progressed, as manifested by decreasing CD4 cell count and increasing HIV RNA (viral load). Since TNF-α is an important component of the innate immune system and is produced upon activation of Toll-like receptor (TLR) pathways, we hypothesized that the mechanism associated with deficient TNF-α production in the lung involved altered TLR expression or a deficit in the TLR signaling cascade. We found decreased Toll-like receptor 1 (TLR1) and TLR4 surface expression in HIV-infected U1 monocytic cells compared to the uninfected parental U937 cell line and decreased TLR message in alveolar macrophages (AMs) from HIV-positive subjects. In addition, stimulation with TLR1/2 ligand (Pam3Cys) or TLR4 ligand (lipopolysaccharide) resulted in decreased intracellular phosphorylated extracellular signal-regulated kinase and subsequent decreased transcription and expression of TNF-α in U1 cells compared to U937 cells. AMs from HIV-positive subjects also showed decreased TNF-α production in response to these TLR2 and TLR4 ligands. We postulate that HIV infection alters expression of TLRs with subsequent changes in mitogen-activated protein kinase signaling and cytokine production that ultimately leads to deficiencies of innate immune responses that predispose HIV-positive subjects to infection.

Download Full-text

Transcription Factor AP-2α Is Preferentially Cleaved by Caspase 6 and Degraded by Proteasome during Tumor Necrosis Factor Alpha-Induced Apoptosis in Breast Cancer Cells

Molecular and Cellular Biology ◽

10.1128/mcb.21.15.4856-4867.2001 ◽

2001 ◽

Vol 21 (15) ◽

pp. 4856-4867 ◽

Cited By ~ 32

Author(s):

Okot Nyormoi ◽

Zhi Wang ◽

Dao Doan ◽

Maribelis Ruiz ◽

David McConkey ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Cells ◽

Tumor Necrosis ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Factor Alpha ◽

Caspase 6 ◽

Induced Apoptosis ◽

Necrosis Factor

ABSTRACT Several reports have linked activating protein 2α (AP-2α) to apoptosis, leading us to hypothesize that AP-2α is a substrate for caspases. We tested this hypothesis by examining the effects of tumor necrosis factor alpha (TNF-α) on the expression of AP-2 in breast cancer cells. Here, we provide evidence that TNF-α downregulates AP-2α and AP-2γ expression posttranscriptionally during TNF-α-induced apoptosis. Both a general caspase antagonist (zVADfmk) and a caspase 6-preferred antagonist (zVEIDfmk) inhibited TNF-α-induced apoptosis and AP-2α downregulation. In vivo tests showed that AP-2α was cleaved by caspases ahead of the DNA fragmentation phase of apoptosis. Recombinant caspase 6 cleaved AP-2α preferentially, although caspases 1 and 3 also cleaved it, albeit at 50-fold or higher concentrations. Activated caspase 6 was detected in TNF-α-treated cells, thus confirming its involvement in AP-2α cleavage. All three caspases cleaved AP-2α at asp19 of the sequence asp-arg-his-asp (DRHD19). Mutating D19 to A19abrogated AP-2α cleavage by all three caspases. TNF-α-induced cleavage of AP-2α in vivo led to AP-2α degradation and loss of DNA-binding activity, both of which were prevented by pretreatment with zVEIDfmk. AP-2α degradation but not cleavage was inhibited in vivo by PS-431 (a proteasome antagonist), suggesting that AP-2α is degraded subsequent to cleavage by caspase 6 or caspase 6-like enzymes. Cells transfected with green fluorescent protein-tagged mutant AP-2α are resistant to TNF-α-induced apoptosis, further demonstrating the link between caspase-mediated cleavage of AP-2α and apoptosis. This is the first report to demonstrate that degradation of AP-2α is a critical event in TNF-α-induced apoptosis. Since the DRHD sequence in vertebrate AP-2 is widely conserved, its cleavage by caspases may represent an important mechanism for regulating cell survival, proliferation, differentiation, and apoptosis.

Download Full-text

In vivo Antitumor Activities of Tumor Necrosis Factor-Alpha

Molecular Basis of Lymphokine Action ◽

10.1007/978-1-4612-4598-8_21 ◽

1987 ◽

pp. 223-232 ◽

Cited By ~ 2

Author(s):

Michael A. Palladino

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Antitumor Activities ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Necrosis Factor

Download Full-text

Enhancement of Methacholine-Evoked Tracheal Contraction Induced by Bacterial Lipopolysaccharides Depends on Epithelium and Tumor Necrosis Factor

Journal of Allergy ◽

10.1155/2012/494085 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

T. Secher ◽

F. Rodrigues Coelho ◽

N. Noulin ◽

A. Lino dos Santos Franco ◽

V. Quesniaux ◽

...

Keyword(s):

Contractile Response ◽

Ex Vivo ◽

Adaptor Protein ◽

Respiratory Pattern ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Bacterial Lipopolysaccharides ◽

Necrosis Factor

Inhaled bacterial lipopolysaccharides (LPSs) induce an acute tumour necrosis factor-alpha (TNF-α-) dependent inflammatory response in the murine airways mediated by Toll-like receptor 4 (TLR4) via the myeloid differentiation MyD88 adaptor protein pathway. However, the contractile response of the bronchial smooth muscle and the role of endogenous TNFα in this process have been elusive. We determined the in vivo respiratory pattern of C57BL/6 mice after intranasal LPS administration with or without the presence of increasing doses of methacholine (MCh). We found that LPS administration altered the basal and MCh-evoked respiratory pattern that peaked at 90 min and decreased thereafter in the next 48 h, reaching basal levels 7 days later. We investigated in controlled ex vivo condition the isometric contraction of isolated tracheal rings in response to MCh cholinergic stimulation. We observed that preincubation of the tracheal rings with LPS for 90 min enhanced the subsequent MCh-induced contractile response (hyperreactivity), which was prevented by prior neutralization of TNFα with a specific antibody. Furthermore, hyperreactivity induced by LPS depended on an intact epithelium, whereas hyperreactivity induced by TNFα was well maintained in the absence of epithelium. Finally, the enhanced contractile response to MCh induced by LPS when compared with control mice was not observed in tracheal rings from TLR4- or TNF- or TNF-receptor-deficient mice. We conclude that bacterial endotoxin-mediated hyperreactivity of isolated tracheal rings to MCh depends upon TLR4 integrity that signals the activation of epithelium, which release endogenous TNFα.

Download Full-text

Low-dose prostacyclin has potent capillary permeability-reducing effect in cat skeletal muscle in vivo

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.273.1.h200 ◽

1997 ◽

Vol 273 (1) ◽

pp. H200-H207 ◽

Cited By ~ 4

Author(s):

A. D. Moller ◽

P. O. Grande

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Vascular Tone ◽

Low Dose ◽

Capillary Permeability ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Necrosis Factor

The dose-response effects of intravenous infusion of prostacyclin on capillary permeability (the capillary filtration coefficient technique), hydrostatic capillary pressure, transcapillary filtration, and vascular tone were analyzed in vivo on cat skeletal muscle from a normal and an increased permeability level. Increased permeability was accomplished by intra-arterial infusion of tumor necrosis factor-alpha or histamine. Permeability effects of bradykinin were also analyzed. Prostacyclin decreased capillary permeability by 8% at a dose of 0.1 ng.kg-1.min-1 and at most by 30% below control attained at 2 ng.kg-1.min-1, also with no effect on vascular tone and hydrostatic capillary pressure. The permeability increase by tumor necrosis factor-alpha and histamine (by 54 and 73%) was more than counteracted by the simultaneous infusion of prostacyclin at 2 ng.kg-1.min-1. The vasodilator effect of tumor necrosis factor-alpha was also restituted. Indomethacin (prostacyclin inhibitor)-induced increase in capillary permeability (25%) was more than restituted by prostacyclin at 2 ng.kg-1.min-1. Surprisingly, bradykinin decreased capillary permeability. We conclude that endogenous prostacyclin may be a physiological regulator of capillary permeability and that low-dose prostacyclin infusion may have clinical relevance in states of increased permeability.

Download Full-text