scholarly journals TNF-α increases sensitivity to LPS in chronically catheterized rats

2001 ◽  
Vol 280 (6) ◽  
pp. H2857-H2862 ◽  
Author(s):  
Masakatsu Goto ◽  
Lucy V. Deriy ◽  
Yong J. Chen ◽  
David W. A. Beno ◽  
Michael R. Uhing ◽  
...  
Keyword(s):  
Blood Lactate ◽  
Severe Trauma ◽  
Interferon Γ ◽  
Bacterial Toxins ◽  
Peak Serum ◽  
Serum Concentrations ◽  
Tnf Α ◽  
Subsequent Exposure ◽  
Ifn Γ ◽  
Factor Α

Patients with severe trauma injury are transiently exposed to increased serum concentrations of tumor necrosis factor-α (TNF-α). These patients are susceptible to the development of multisystem organ failure (MSOF) triggered by subsequent exposure to bacterial toxins either via infection or increased intestinal permeability. We simulated the cytokine response of trauma by infusing 0.8 or 8.0 μg/kg of TNF-α (priming dose) into chronically catheterized rats. After 48 h, rats were challenged with endotoxin [lipopolysaccharide (LPS); 10 or 1,000 μg/kg]. Animals primed with either dose of TNF-α and then challenged with 1,000 μg/kg of LPS demonstrated significantly increased mortality, mean peak serum concentrations of interferon-γ (IFN-γ), and blood lactate concentrations ( P < 0.05) compared with nonprimed animals. Mean peak serum concentrations of IFN-γ and blood lactate concentrations were increased after challenge with 10 μg/kg of LPS only in animals primed with 8.0 μg/kg of TNF-α. Priming with TNF-α did not increase mortality after challenge with 10 μg/kg of LPS. These data suggest that both TNF-α release and the subsequent exposure to bacterial toxins mediate the pathophysiological progression from trauma to subsequent MSOF.

Regulation of intracellular polyamine biosynthesis and transport by NO and cytokines TNF-α and IFN-γ

1999 ◽  
Vol 276 (4) ◽  
pp. C892-C899 ◽  
Author(s):  
Joseph Satriano ◽  
Shunji Ishizuka ◽  
D. Clay Archer ◽  
Roland C. Blantz ◽  
Carolyn J. Kelly
Keyword(s):  
Cellular Proliferation ◽  
Interferon Γ ◽  
Experimental Models ◽  
Proximal Tubule Cell ◽  
Polyamine Biosynthesis ◽  
No Donors ◽  
Temporal Regulation ◽  
Tnf Α ◽  
Ifn Γ ◽  
Factor Α

Nitric oxide (NO) has been described to exert cytostatic effects on cellular proliferation; however the mechanisms responsible for these effects have yet to be fully resolved. Polyamines, conversely, are required components of cellular proliferation. In experimental models of inflammation, a relationship between these two pathways has been suggested by the temporal regulation of a common precursor, arginine. This study was undertaken to determine the effects NO and the NO synthase (NOS)-inducing cytokines, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), exert on polyamine regulation. The transformed kidney proximal tubule cell line, MCT, maintains high constitutive levels of the first polyamine biosynthetic enzyme, ornithine decarboxylase (ODC). NO donors markedly suppressed ODC activity in MCT and all other cell lines examined. TNF-α and IFN-γ induction of NO generation resulted in suppressed ODC activity, an effect prevented by the inducible NOS inhibitorl- N 6-(1-iminoethyl)lysine (l-NIL). Dithiothreitol reversal of NO-mediated ODC suppression supports nitrosylation as the mechanism of inactivation. We also evaluated polyamine uptake, inasmuch as inhibition of ODC can result in a compensatory induction of polyamine transporters. Administration of NO donors, or TNF-α and IFN-γ, suppressed [3H]putrescine uptake, thereby preventing transport-mediated reestablishment of intracellular polyamine levels. This study demonstrates the capacity of NO and inflammatory cytokines to regulate both polyamine biosynthesis and transport.

Mesenchymal stromal cell plasticity and the tumor microenvironment

2017 ◽  
Vol 1 (5) ◽  
pp. 487-492
Author(s):  
Hee Joon Bae ◽  
Shutong Liu ◽  
Ping Jin ◽  
David Stroncek
Keyword(s):  
Tumor Microenvironment ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Tumor Infiltrating Lymphocytes ◽  
Transforming Growth Factor Β ◽  
Interferon Γ ◽  
Tnf Α ◽  
Ifn Γ ◽  
Factor Α ◽  
Infiltrating Lymphocytes

Mesenchymal stem cells or mesenchymal stromal cells (MSCs) are a multipotent, heterogeneous population of cells that play a critical role in wound healing and tissue regeneration. MSCs, found in the tumor microenvironment, support tumor growth through the production of angiogenic factors, growth factors and extracellular matrix proteins. They also have immunomodulatory properties, and since they produce indoleamine 2,3-dioxygenase (IDO), prostaglandin E2 (PGE2) and transforming growth factor β (TGF-β), they have been thought to have primarily immunosuppressive effects. However, their role in the tumor microenvironment is complex and demonstrates plasticity depending on location, stimulatory factors and environment. The presence of melanoma-activated tumor-infiltrating lymphocytes (TILs) has been shown to produce pro-inflammatory changes with TH1 (type 1T helper)-like phenotype in MSCs via activated-TIL released cytokines such as interferon γ (IFN-γ), tumor necrosis factor α (TNF-α) and interleukin-1α (IL-1α), while simultaneously producing factors, such as IDO1, which have been traditionally associated with immunosuppression. Similarly, the combination of IFN-γ and TNF-α polarizes MSCs to a primarily TH1-like phenotype with the expression of immunosuppressive factors. Ultimately, further studies are encouraged and needed for a greater understanding of the role of MSCs in the tumor microenvironment and to improve cancer immunotherapy.

scholarly journals Intracellular Antimicrobial Activity in the Absence of Interferon-γ: Effect of Interleukin-12 in Experimental Visceral Leishmaniasis in Interferon-γ Gene-disrupted Mice

1997 ◽  
Vol 185 (7) ◽  
pp. 1231-1240 ◽  
Author(s):  
Alice P. Taylor ◽  
Henry W. Murray
Keyword(s):  
Antimicrobial Activity ◽  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Gene Knockout ◽  
Interferon Γ ◽  
Interleukin 12 ◽  
Tnf Α ◽  
Ifn Γ ◽  
Independent Effects ◽  
Factor Α

Despite permitting uncontrolled intracellular visceral infection for 8 wk, interferon-γ (IFN-γ) gene knockout (GKO) mice infected with Leishmania donovani proceeded to reduce liver parasite burdens by 50% by week 12. This late-developing IFN-γ–independent antileishmanial mechanism appeared to be dependent largely on endogenous tumor necrosis factor-α (TNF-α): L. donovani infection induced TNF-α mRNA expression in parasitized GKO livers and neutralization of TNF-α reversed control at week 12. 7 d of treatment of infected GKO mice with interleukin-12 (IL-12) readily induced leishmanicidal activity and also partially restored the near-absent tissue granulomatous response, observations that for the first time expand the antimicrobial repertoire of IL-12 to include IFN-γ–independent effects. The action of IL-12 against L. donovani was TNF-α dependent and required the activity of inducible nitric oxide synthase. These results point to the presence of an IFN-γ–independent antimicrobial mechanism, mediated by TNF-α, which remains quiescent until activated late in the course of experimental visceral leishmaniasis. However, as judged by the effect of exogenous IL-12 this quiescent mechanism can readily be induced to rapidly yield enhanced intracellular antimicrobial activity.

Selective suppression of IL-12 production by human herpesvirus 6

Blood ◽  
2003 ◽  
Vol 102 (8) ◽  
pp. 2877-2884 ◽  
Author(s):  
Alison Smith ◽  
Fabio Santoro ◽  
Giulia Di Lullo ◽  
Lorenzo Dagna ◽  
Alessia Verani ◽  
...  
Keyword(s):  
Human Herpesvirus ◽  
Interferon Γ ◽  
Immunosuppressive Agent ◽  
Interleukin 12 ◽  
Human Herpesvirus 6 ◽  
Rnase Protection ◽  
Tnf Α ◽  
Ifn Γ ◽  
Herpesvirus 6 ◽  
Factor Α

Abstract Human herpesvirus 6 (HHV-6) is a potentially immunosuppressive agent that has been suggested to act as a cofactor in the progression of HIV disease. Exposure of human macrophages to HHV-6A or HHV-6B profoundly impaired their ability to produce interleukin 12 (IL-12) upon stimulation with interferon-γ (IFN-γ) and lipopolysaccharide (LPS). By contrast, the production of tumor necrosis factor–α (TNF-α); regulated on activation, normal T-cell expressed and secreted (RANTES); and macrophage inflammatory protein 1β (MIP-1β) was not negatively affected. To exclude the involvement of IL-12–suppressive cytokines, such as IL-10 and TNF-α, the viral stocks were fractionated by ultra-centrifugation. The bulk of the suppressive activity was recovered within the virion-rich pelleted fraction that was virtually devoid of such cytokines. IL-12 suppression was independent of viral replication, and the effect was not abrogated upon ultraviolet-light inactivation of the viral inoculum. The mechanism of HHV-6–mediated IL-12 suppression was investigated by RNase protection assays, which demonstrated unaltered levels of IL-12 p35 mRNA and only a modest reduction in p40 mRNA, which was insufficient to account for the near-complete loss of both extracellular and intracellular IL-12 protein. Moreover, both the IFN-γ and the LPS signaling pathways were intact in HHV-6–treated cells. These data suggest that HHV-6 can dramatically affect the generation of effective cellular immune responses, providing a novel potential mechanism of HHV-6–mediated immunosuppression.

Systemic Sclerosis Fibroblasts Show Specific Alterations of Interferon-γ and Tumor Necrosis Factor-α-induced Modulation of Interleukin 6 and Chemokine Ligand 2

2012 ◽  
Vol 39 (5) ◽  
pp. 979-985 ◽  
Author(s):  
ALESSANDRO ANTONELLI ◽  
POUPAK FALLAHI ◽  
SILVIA MARTINA FERRARI ◽  
DILIA GIUGGIOLI ◽  
MICHELE COLACI ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Tumor Necrosis Factor ◽  
Interleukin 6 ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Interferon Γ ◽  
Tnf Α ◽  
Ifn Γ ◽  
Factor Α ◽  
Necrosis Factor

Objective.We evaluated the effect of interferon-γ (IFN-γ) and/or tumor necrosis factor-α (TNF-α) on the secretion of prototype proinflammatory cytokine interleukin 6 (IL-6), compared to T-helper 1 [Th1; chemokine (C-X-C motif) ligand 10 (CXCL10)] or Th2 [chemokine (C-C motif) ligand 2 (CCL2)] chemokines, in primary cultured fibroblasts from patients with systemic sclerosis (SSc) at an early stage of the disease.Methods.Fibroblast cultures from 5 SSc patients (disease duration < 2 yrs) and 5 healthy controls were evaluated for the production of IL-6, CXCL10, and CCL2 at the basal level and after stimulation with IFN-γ and/or TNF-α.Results.SSc fibroblasts basally produced higher levels of IL-6 than controls, while no difference was observed about CCL2 and CXCL10. TNF-α was able to dose-dependently induce IL-6 and CCL2 secretion in SSc, but not in control fibroblasts. By stimulation with increasing doses of IFN-γ, SSc fibroblasts were induced to secrete CCL2 and CXCL10, while no effect was observed on IL-6. The combination of IFN-γ and TNF-α induced a strong secretion of IL-6 and CCL2 in SSc fibroblasts but not in controls. In contrast, the synergistic effect of IFN-γ and TNF-α on CXCL10 secretion was similar in SSc fibroblasts and in controls.Conclusion.SSc fibroblasts participate in the self-perpetuation of inflammation by releasing IL-6, CXCL10, and CCL2 under the influence of IFN-γ and/or TNF-α. SSc fibroblasts are more active than controls in the secretion of IL-6 at baseline, and in the production of IL-6 and CCL2 under the combined IFN-γ/TNF-α stimulation.

scholarly journals Proinflammatory cytokines tumor necrosis factor-α and interferon-γ alter tight junction structure and function in the rat parotid gland Par-C10 cell line

2008 ◽  
Vol 295 (5) ◽  
pp. C1191-C1201 ◽  
Author(s):  
Olga J. Baker ◽  
Jean M. Camden ◽  
Robert S. Redman ◽  
Jonathan E. Jones ◽  
Cheikh I. Seye ◽  
...  
Keyword(s):  
Receptor Agonist ◽  
Interferon Γ ◽  
Anion Secretion ◽  
Cell Monolayers ◽  
Tnf Α ◽  
Rat Parotid Gland ◽  
Ifn Γ ◽  
Rat Parotid ◽  
Factor Α ◽  
Necrosis Factor

Sjögren's syndrome (SS) is an autoimmune disorder characterized by inflammation and dysfunction of salivary glands, resulting in impaired secretory function. The production of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) is elevated in exocrine glands of patients with SS, although little is known about the effects of these cytokines on salivary epithelial cell functions necessary for saliva secretion, including tight junction (TJ) integrity and the establishment of transepithelial ion gradients. The present study demonstrates that chronic exposure of polarized rat parotid gland (Par-C10) epithelial cell monolayers to TNF-α and IFN-γ decreases transepithelial resistance (TER) and anion secretion, as measured by changes in short-circuit current ( Isc) induced by carbachol, a muscarinic cholinergic receptor agonist, or UTP, a P2Y2 nucleotide receptor agonist. In contrast, TNF-α and IFN-γ had no effect on agonist-induced increases in the intracellular calcium concentration [Ca2+]i in Par-C10 cells. Furthermore, treatment of Par-C10 cell monolayers with TNF-α and IFN-γ increased paracellular permeability to normally impermeant proteins, altered cell and TJ morphology, and downregulated the expression of the TJ protein, claudin-1, but not other TJ proteins expressed in Par-C10 cells. The decreases in TER, agonist-induced transepithelial anion secretion, and claudin-1 expression caused by TNF-α, but not IFN-γ, were reversible by incubation of Par-C10 cell monolayers with cytokine-free medium for 24 h, indicating that IFN-γ causes irreversible inhibition of cellular activities associated with fluid secretion in salivary glands. Our results suggest that cytokine production is an important contributor to secretory dysfunction in SS by disrupting TJ integrity of salivary epithelium.

scholarly journals Interferon γ induces differential upregulation of α and β chemokine secretion in colonic epithelial cell lines

Gut ◽  
1998 ◽  
Vol 42 (2) ◽  
pp. 208-213 ◽  
Author(s):  
A C Warhurst ◽  
S J Hopkins ◽  
G Warhurst
Keyword(s):  
Cell Lines ◽  
Inflammatory Cells ◽  
Interferon Γ ◽  
Inflammatory Protein ◽  
Chemotactic Protein ◽  
Tnf Α ◽  
Activated T Lymphocytes ◽  
Ifn Γ ◽  
Significant Expression ◽  
Factor Α

Background—Production of chemoattractant factors by the intestinal epithelium may contribute to mucosal infiltration by inflammatory cells in inflammatory bowel disease. Secretion of the α chemokine interleukin 8 (IL-8), a neutrophil chemoattractant, has been widely studied, but little is known about epithelial secretion of β chemokines, which are preferentially involved in recruiting monocytes.Aims—To investigate the profiles of α and β chemokine secretion in colonic cell lines and their differential modulation by interferon γ (IFN-γ), a product of activated T lymphocytes and natural killer cells.Methods and results—HT29-19A, a model of the Cl− secretory crypt cell, exhibited a parallel secretion of the α chemokines IL-8 and GROα, which could be markedly upregulated by tumour necrosis factor α (TNF-α) and IL-1β. These cells showed no significant expression of the β chemokines RANTES (regulated upon activation T cell expressed and secreted), MIP-1α (macrophage inflammatory protein 1α), and MCP-1 (monocyte chemotactic protein 1) under these conditions, but IFN-γ in combination with TNF-α caused a dose dependent induction of RANTES and MCP-1 secretion. This was accompanied by a marked increase of RANTES mRNA. In contrast, IFN-γ had no significant effect on TNF-α stimulated IL-8 secretion. Caco-2 cells, with features more typical of villus absorptive cells, were relatively poor secretors of α chemokines but secreted high levels of MCP-1 in response to IL-1β. IFN-γ did not influence α or β chemokine secretion in these cells.Conclusions—These studies suggest that intestinal epithelial cells may produce chemokines capable of attracting both neutrophils and monocytes. The ability of IFN-γ to activate the expression of β chemokines preferentially could facilitate the development of chronic inflammatory infiltrates.

Human intestinal intraepithelial lymphocytes and epithelial cells coinduce interleukin-8 production through the CD2-CD58 interaction

2009 ◽  
Vol 296 (3) ◽  
pp. G671-G677 ◽  
Author(s):  
Ellen C. Ebert ◽  
Asit Panja ◽  
Rajalakshmi Praveen
Keyword(s):  
Epithelial Cells ◽  
Cell Types ◽  
Interferon Γ ◽  
Intraepithelial Lymphocytes ◽  
Cell Contact ◽  
Tnf Α ◽  
Active Transcription ◽  
Ifn Γ ◽  
Factor Α ◽  
Ht 29

Human intestinal CD3+TCRαβ+CD8+ intraepithelial lymphocytes (IELs) are intimately associated with epithelial cells (ECs) through binding of CD103 to E-cadherin. How these two cell types functionally interact is largely unknown. IEL-EC cross talk was determined using HT-29 cells as the model EC and IL-8 as the readout. IL-8 was derived from both cell types and synergistically increased when the cells were combined. This synergistic effect required active transcription by both IELs and HT-29 cells. Cell contact was required as shown by the loss of the synergistic increase in IL-8 when the two cell types were separated by Transwells. Specifically, IL-8 release required the binding of CD2 on the IELs to CD58 on the HT-29 cells. The association of the CD3/TCR complex with major histocompatibility antigen class I antigens was not involved. Antibody neutralization of tumor necrosis factor-α (TNF-α), but not interferon-γ (IFN-γ), resulted in increased IL-8 production by the coculture. Although both TNF-α and IFN-γ increased IL-8 synthesis and CD58 expression by the HT-29 cells, only IFN-γ reduced IL-8 production by IELs. IL-8 production by either cell type involved phosphorylation of p38 and JNK. In summary, the synergistic synthesis of IL-8 occurs when IELs are stimulated through the CD2 pathway by CD58 on HT-29 cells, resulting in TNF-α release that, in turn, augments IL-8 synthesis and CD58 expression by the HT-29 cells.

High Serum Levels of CXCL11 in Mixed Cryoglobulinemia Are Associated with Increased Circulating Levels of Interferon-γ

2011 ◽  
Vol 38 (9) ◽  
pp. 1947-1952 ◽  
Author(s):  
ALESSANDRO ANTONELLI ◽  
CLODOVEO FERRI ◽  
SILVIA MARTINA FERRARI ◽  
ILARIA RUFFILLI ◽  
MICHELE COLACI ◽  
...  
Keyword(s):  
Strong Relationship ◽  
Serum Levels ◽  
Mixed Cryoglobulinemia ◽  
Interferon Γ ◽  
High Serum ◽  
Hepatitis C Infection ◽  
T Helper 1 ◽  
Tnf Α ◽  
Ifn Γ ◽  
Factor Α

Objective.No study has evaluated circulating chemokine C-X-C motif ligand (CXCL)11 in patients with “mixed cryoglobulinemia and chronic hepatitis C infection” (MC+HCV). We measured CXCL11, and correlated this measurement to the clinical phenotype.Methods.Serum CXCL11, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) were assayed in 97 MC+HCV patients and in 97 sex- and age-matched controls.Results.MC+HCV patients showed significantly higher mean CXCL11 serum levels than controls (254 ± 295, 68 ± 16 pg/ml, respectively; p = 0.0002; ANOVA). CXCL11 was significantly increased in 36 cryoglobulinemic patients with compared to those without active vasculitis (303 ± 208 vs 179 ± 62 pg/ml, respectively; p < 0.001; ANOVA). IFN-γ levels were significantly higher in MC+HCV than in controls [6.1 (range 0.8–114.5), 1.4 (range 0.7–2.4) pg/ml, respectively; p < 0.05; Mann-Whitney U test]. Serum TNF-α mean levels were significantly higher in MC+HCV than in controls [13.4 (range 1.8–369), 1.1 (range 0.7–3.2) pg/ml, respectively; p < 0.0001; Mann-Whitney U test]. A multiple regression analysis considering CXCL11 as a dependent variable, and age, alanine aminotransferase, IFN-γ, and TNF-α as independent variables, showed in MC+HCV patients a significant association only with IFN-γ (p < 0.0001).Conclusion.Our study demonstrates markedly high serum levels of CXCL11 in patients with MC+HCV compared to healthy controls overall in the presence of active vasculitis. A strong relationship between circulating IFN-γ and CXCL11 was shown, strongly supporting the role of a T helper 1 immune response in the pathogenesis of MC+HCV.

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