scholarly journals TIR-Domain-Containing Adaptor-Inducing Interferon-β (TRIF) Mediates Antibacterial Defense during Gram-Negative Pneumonia by Inducing Interferon-γ

2015 ◽  
Vol 7 (6) ◽  
pp. 637-646 ◽  
Author(s):  
Miriam H.P. van Lieshout ◽  
Sandrine Florquin ◽  
Cornelis vanʼt Veer ◽  
Alex F. de Vos ◽  
Tom van der Poll
Keyword(s):  
Interferon Γ ◽  
Primary Response ◽  
Mutant Mice ◽  
Klebsiella Pneumonia ◽  
Hepatocellular Injury ◽  
Interferon Β ◽  
Gram Negative ◽  
Tir Domain ◽  
Ifn Γ

Klebsiella pneumoniae is an important cause of Gram-negative pneumonia and sepsis. Mice deficient for TIR-domain-containing adaptor-inducing interferon-β (TRIF) demonstrate enhanced bacterial growth and dissemination during Klebsiella pneumonia. We show here that the impaired antibacterial defense of TRIF mutant mice is associated with absent interferon (IFN)-γ production in the lungs. IFN-γ production by splenocytes in response to K. pneumoniae in vitro was critically dependent on Toll-like receptor 4 (TLR4), the common TLR adaptor myeloid differentiation primary response gene (MyD88) and TRIF. Reconstitution of TRIF mutant mice with recombinant IFN-γ via the airways reduced bacterial loads in lungs and distant body sites to levels measured in wild-type mice, and partially restored pulmonary cytokine levels. The IFN-γ-induced, improved, enhanced antibacterial response in TRIF mutant mice occurred at the expense of increased hepatocellular injury. These data indicate that TRIF mediates antibacterial defense during Gram-negative pneumonia, at least in part, by inducing IFN-γ at the primary site of infection.

A Summary of the Third Global Interferon-γ Release Assay Symposium

2013 ◽  
Vol 34 (6) ◽  
pp. 619-624 ◽  
Author(s):  
Antonino Catanzaro ◽  
Charles Daley
Keyword(s):  
Immune Response ◽  
Tuberculin Skin Test ◽  
Skin Test ◽  
Interferon Γ ◽  
Enzyme Linked Immunosorbent Assay ◽  
In Vitro Tests ◽  
The Third ◽  
Specific Antigens ◽  
Ifn Γ

Studies over the past several decades have dramatically increased our understanding of the immune response to Mycobacterium tuberculosis infection, and advances in proteomics and genomics have led to a new class of immune-diagnostic tests, termed interferon-γ (IFN-γ) release assays (IGRAs), which appear to obviate many of the problems encountered with the tuberculin skin test (TST). Worldwide, 2 IGRAs are currently commercially available. QuantiFERON-TB Gold In-Tube (Cellestis) is a third-generation product that uses an enzyme-linked immunosorbent assay to measure IFN-γ generated in whole blood stimulated with M. tuberculosis–specific antigens. T-Spot-TB (Oxford Immunotec) employs enzyme-linked immunosorbent spot technology to enumerate the number of purified lymphocytes that respond to M. tuberculosis–specific antigens by producing IFN-γ. These in vitro tests measure the host immune response to M. tuberculosis–specific antigens, which virtually eliminates false-positive cross reactions caused by bacillus Calmette-Guérin vaccination and/or exposure to environmental nontuberculous mycobacteria that plague the interpretation and accuracy of the tuberculin skin test (TST). The high specificity of IGRAs, together with sensitivity commensurate with or better than that of the TST, promises an accurate diagnosis and the ability to focus tuberculosis-control activities on those who are actually infected with M. tuberculosis. The Third Global Symposium was held over a 3-day period and was presented by the University of California, San Diego, Continuing Medical Education department; slides and sound recordings of each presentation are available at http://cme.ucsd.edu/igras/syllabus.html. A moderated discussion is also available at http://cme.ucsd.edu/igrasvideo. This document provides a summary of the key findings of the meeting, specifically focusing on the use of IGRAs in screening healthcare worker populations.

scholarly journals Effect ofTityus serrulatusvenom on cytokine production and the activity of murine macrophages

2002 ◽  
Vol 11 (1) ◽  
pp. 23-31 ◽  
Author(s):  
Vera L. Petricevich
Keyword(s):  
Cytokine Production ◽  
Peritoneal Macrophages ◽  
Interferon Γ ◽  
Enzyme Linked Immunosorbent Assay ◽  
No Production ◽  
Dependent Manner ◽  
Immune Functions ◽  
Macrophage Activity ◽  
Ifn Γ

The purpose of this study was to investigate the effects ofTityus serrulatusvenom (TSV) on murine peritoneal macrophages evaluated in terms of activation. The effects of crude TSV were analysed by detection of cytokines, oxygen intermediate metabolites (H2O2) and nitric oxide (NO) in supernatants of peritoneal macrophages. Several functional bioassays were employed including anin vitromodel for envenomating: cytotoxicity of TSV was assessed using the lyses percentage. Tumor necrosis factor (TNF) activity was assayed by measuring its cytotoxic activity on L-929 cells, and interleukin-6 (IL-6) and interferon-γ (IFN-γ) were assayed by enzyme-linked immunosorbent assay, whereas NO levels were detected by Griess colorimetric reactions in culture supernatant of macrophages incubated with TSV and subsequently exposed to either lipopolysaccharide or IFN-γ. Incubation of macrophages with TSV increased production of IL-6 and IFN-γ in a dose-dependent manner. TNF production was not detected in supernatants treated with TSV at any concentration. The increase in IL-6 secretion was not associated with concentration-dependent cytoxicity of TSV on these cells. These data suggest that the cytotoxicity does not appear to be the main cause of an increased cytokine production by these cells. Although NO is an important effector molecule in macrophage microbicidal activity, the inducing potential of the test compounds for its release was found to be very moderate, ranging from 125 to 800 mM. Interestingly, NO levels of peritoneal macrophages were increased after IFN-γ. Moreover, NO production had an apparent effect on macrophage activity. The results obtained here also shown that the TSV induces an important elevation in H2O2release. These results combined with NO production suggest that TSV possesses significant immunomodulatory activities capable of stimulating immune functionsin vitro.

scholarly journals Spontaneous secretion of interferon γ and interleukin 4 by human intraepithelial and lamina propria gut lymphocytes

Gut ◽  
1998 ◽  
Vol 42 (5) ◽  
pp. 643-649 ◽  
Author(s):  
M Carol ◽  
A Lambrechts ◽  
A Van Gossum ◽  
M Libin ◽  
M Goldman ◽  
...  
Keyword(s):  
Lamina Propria ◽  
Intestinal Mucosa ◽  
Mononuclear Cells ◽  
Critical Role ◽  
Gastrointestinal Diseases ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Peripheral Blood Mononuclear ◽  
Ifn Γ

Background—Cytokines secreted by intestinal T lymphocytes probably play a critical role in regulation of the gut associated immune responses.Aims—To quantify interferon γ (IFN-γ) and interleukin 4 (IL-4) secreting cells (SC) among human intraepithelial (IEL) and lamina propria (LPL) lymphocytes from the duodenum and right colon in non-pathological situations and in the absence of in vitro stimulation.Patients—Duodenal and right colonic biopsy specimens were obtained from patients with no inflammation of the intestinal mucosa.Methods—Intraepithelial and lamina propria cell suspensions were assayed for numbers of cells spontaneously secreting IFN-γ and IL-4 by a two site reverse enzyme linked immunospot technique (ELISPOT).Results—The relatively high proportion of duodenal lymphocytes spontaneously secreting IFN-γ (IEL 3.6%; LPL 1.9%) and IL-4 (IEL 1.3%; LPL 0.7%) contrasted with the very low numbers of spontaneously IFN-γ SC and the absence of spontaneously IL-4 SC among peripheral blood mononuclear cells. In the basal state, both IFN-γ and IL-4 were mainly produced by CD4+ cells. Within the colon, only 0.2% of IEL and LPL secreted IFN-γ in the basal state, and 0.1% secreted IL-4.Conclusions—Compared with peripheral lymphocytes substantial proportions of intestinal epithelial and lamina propria lymphocytes spontaneously secrete IFN-γ and/or IL-4. These cytokines are probably involved in the normal homoeostasis of the human intestinal mucosa. Disturbances in their secretion could play a role in the pathogenesis of gastrointestinal diseases.

scholarly journals Production of interferon-γ by natural killer cells and aging in chronic human schistosomiasis

2004 ◽  
Vol 13 (5-6) ◽  
pp. 327-333 ◽  
Author(s):  
E. Speziali ◽  
J. Bethony ◽  
O. Martins-Filho ◽  
L. A. O. Fraga ◽  
D. S. Lemos ◽  
...  
Keyword(s):  
Natural Killer Cells ◽  
Natural Killer ◽  
Infection Intensity ◽  
The Elderly ◽  
Interferon Γ ◽  
Older Individuals ◽  
Killer Cells ◽  
Human Schistosomiasis ◽  
Ifn Γ

BACKGROUNG: Aging is associated with several alterations in the phenotype, repertoire and activation status of lymphocytes as well as in the cytokine profile produced by these cells. As a lifelong condition, chronic parasitic diseases such as human schistosomiasis overlaps with the aging process and no systematic study has yet addressed the changes in immune response during infection withSchistosoma mansoniin older individuals.Aim: Herein we study the influence of immunological alterations brought about by senescence in the course of schistosomiasis.Materials and methods: Individuals 10-95 years of age, from both sexes, from an endemic area forS. mansoniinfection were matched by intensity of infection as measured by egg counts. We analyzed, as a parameter, cytokine expression by lymphocytes and natural killer cells afterin vitrostimulation with soluble egg antigen and soluble worm antigen using flow cytometry.Results: We demonstrated that the frequency of CD16+interferon-γ (IFN-γ)+natural killer cells in negative individuals over the age of 70 years is significantly higher than in positive individuals afterin vitrostimulation withS. mansoniantigen extracts. The frequency of these cells is increased in all individuals over the age of 50 years and only declines in positive individuals after 70 years of age. Analysis of either CD4?or CD8?cells after antigen stimulation show no significant increase in frequency of IFN-γ in negative or in positive individuals of this age group, suggesting that the effect on CD16+cells is not T-cell dependent.Conclusion: Since production of IFN-γ has been related to resistance to schistosome infection, our data suggest that age-associated changes in CD16+cells may play a role in controlling infection intensity in the elderly inS. mansoniendemic areas of Brazil.

scholarly journals Synergistic interactions between interferon-γ and TRAIL modulate c-FLIP in endothelial cells, mediating their lineage-specific sensitivity to thrombotic thrombocytopenic purpura plasma–associated apoptosis

Blood ◽  
2008 ◽  
Vol 112 (2) ◽  
pp. 340-349 ◽  
Author(s):  
Radu Stefanescu ◽  
Dustin Bassett ◽  
Rozbeh Modarresi ◽  
Francisco Santiago ◽  
Mohamad Fakruddin ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Interferon Γ ◽  
Microvascular Endothelial Cell ◽  
Caspase 8 ◽  
Inhibitory Protein ◽  
Thrombocytopenic Purpura ◽  
Ifn Γ ◽  
Interfering Rna

Abstract Microvascular endothelial cell (MVEC) injury coupled to progression of platelet microthrombi facilitated by ADAMTS13 deficiency is characteristic of idiopathic and HIV-linked thrombotic thrombocytopenic purpura (TTP). Cytokines capable of inducing MVEC apoptosis in vitro are up-regulated in both TTP and HIV infection. However, the concentrations of these cytokines required to elicit EC apoptosis in vitro are 2- to 3-log–fold greater than present in patient plasmas. We report that clinically relevant levels of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and interferon (IFN)–γ act in synergy to induce apoptosis in dermal MVECs, but have no effect on large-vessel ECs or pulmonary MVECs. This reflects the tissue distribution of TTP lesions in vivo. Sensitivity to TTP plasma or TRAIL plus IFN-γ is paralleled by enhanced ubiquitination of the caspase-8 regulator cellular FLICE-like inhibitory protein (c-FLIP), targeting it for proteasome degradation. c-FLIP silencing with anti-FLIP short interfering RNA (siRNA) in pulmonary MVECs rendered them susceptible to TTP plasma– and cytokine-mediated apoptosis, while up-regulation of c-FLIP by gene transfer partially protected dermal MVECs from such injury. TTP plasma–mediated apoptosis appears to involve cytokine-induced acceleration of c-FLIP degradation, sensitizing cells to TRAIL-mediated caspase-8 activation and cell death. Suppression of TRAIL or modulation of immunoproteasome activity may have therapeutic relevance in TTP.

Effects of the Japanese herbal medicine ‘Inchinko-to’ (TJ-135) on concanavalin A-induced hepatitis in mice

2000 ◽  
Vol 99 (5) ◽  
pp. 421-431 ◽  
Author(s):  
Masayoshi YAMASHIKI ◽  
Akihito MASE ◽  
Ichiro ARAI ◽  
Xian-Xi HUANG ◽  
Tsutomu NOBORI ◽  
...  
Keyword(s):  
Herbal Medicine ◽  
Concanavalin A ◽  
Serum Levels ◽  
Interferon Γ ◽  
Hepatic Necrosis ◽  
Interleukin 12 ◽  
Con A ◽  
Ifn Γ

Inchinko-to (TJ-135) is a herbal medicine consisting of three kinds of crude drugs, and in Japan it is administered mainly to patients with cholestasis. The present study evaluated the effects of TJ-135 on concanavalin A (con A)-induced hepatitis in mice in vivo and con A-induced cytokine production in vitro. When mice were pretreated with oral TJ-135 for 1 week before intravenous con A injection, the activities of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) were significantly decreased 8 h after con A administration (-82%, -96% and -66% respectively). In histological investigations, sub-massive hepatic necrosis accompanying inflammatory cell infiltration was not observed in mice pretreated with TJ-135. Serum levels of interleukin-12 (IL-12), interferon-γ (IFN-γ) and IL-2 were significantly lower in mice pretreated with TJ-135 compared with controls, while IL-10 levels were higher in these mice. Intrasplenic IL-12 levels were significantly lower in mice pretreated with TJ-135, while intrasplenic IL-10 levels were higher in these mice. In vitro, IL-10 production by splenocytes was increased by the addition of TJ-135 to the culture medium, whereas the production of IL-12 and IFN-γ was inhibited. These results suggest that con A-induced hepatitis was ameliorated by pretreatment with TJ-135. With regard to the mechanism of these effects of TJ-135, we speculate that TJ-135 inhibits the production of inflammatory cytokine and enhances the production of anti-inflammatory cytokines. Therefore administration of TJ-135 may be useful in patients with severe acute hepatitis accompanying cholestasis or in those with autoimmune hepatitis.

scholarly journals Effect of isoniazid on antigen-specific interferon-γ secretion in latent tuberculosis

2014 ◽  
Vol 45 (2) ◽  
pp. 473-482 ◽  
Author(s):  
Martha Torres ◽  
Lourdes García-García ◽  
Pablo Cruz-Hervert ◽  
Heinner Guio ◽  
Claudia Carranza ◽  
...  
Keyword(s):  
Latent Tuberculosis ◽  
Peptide Pool ◽  
Interferon Γ ◽  
Treatment Regimes ◽  
Latent Tb ◽  
Ifn Γ ◽  
New Treatment ◽  
Latent Tb Infection ◽  
Culture Filtrate Protein

Treatment of persons with latent tuberculosis (TB) infection at greatest risk of reactivation is an important component of TB control and elimination strategies. Biomarkers evaluating the effectiveness of treatment of latent TB infection have not yet been identified. This information would enhance control efforts and assist the evaluation of new treatment regimes.We designed a two-group, two-arm, randomised clinical study of tuberculin skin test-positive participants: 26 with documented contact with TB patients and 34 with non-documented contact. Participants in each group were randomly assigned to the immediate- or deferred-isoniazid treatment arms. Assays ofin vitrointerferon (IFN)-γ secretion in response to recombinant Rv1737 and overlapping synthetic peptide pools from various groups of immunodominant proteins were performed.During isoniazid therapy, a significant increase from baseline in the proportion of IFN-γ responders to the 10-kDa culture filtrate protein, Rv2031, Rv0849, Rv1986, Rv2659c, Rv2693c and the recombinant Rv1737 protein was observed (p⩽0.05). The peptide pool of Rv0849 and Rv1737 recombinant proteins induced the highest percentage of IFN-γ responders after isoniazid therapy.Thein vitroIFN-γ responses to these proteins might represent useful markers to evaluate changes associated with treatment of latent TB infection.

Characterization of the human intestinal CD98 promoter and its regulation by interferon-γ

2007 ◽  
Vol 292 (2) ◽  
pp. G535-G545 ◽  
Author(s):  
Yutao Yan ◽  
Guillaume Dalmasso ◽  
Shanthi Sitaraman ◽  
Didier Merlin
Keyword(s):  
Transcriptional Regulation ◽  
Intestinal Inflammation ◽  
Direct Sequencing ◽  
Interferon Γ ◽  
Initiation Site ◽  
Start Codon ◽  
Transcriptional Initiation ◽  
Ifn Γ

Growing evidence that epithelial CD98 plays an important role in intestinal inflammation focused our interest to investigate the transcriptional regulation of CD98. Our mouse-based in vivo and in vitro experiments revealed that epithelial colonic CD98 mRNA expression was transcriptionally increased in intestinal inflammation. We then isolated and characterized a 5′-flanking fragment containing the promoter region required for CD98 gene transcription. Primer extension and rapid amplification of 5′-cDNA ends were used to map a transcriptional initiation site 129 bp upstream from the translational start codon (ATG). Direct sequencing of the 5′-flanking region revealed the presence of four GC-rich stimulating protein (Sp)1 binding domains, one NF-κB binding domain, and no TATA box. Binding of Sp1 [Sp1(−874), SP1(−386), Sp1(−187), and Sp1(−177)] and NF-κB [NF-κB(−213)] to the promoter was confirmed by EMSA and supershift assays. Furthermore, chromatin immunoprecipitation experiments showed the in vivo DNA-Sp1 and DNA-NF-κB interactions under basal and IFN-γ-stimulated conditions. Reporter genes driven by serially truncated and site-mutated CD98 promoters were used to examine basal and IFN-γ-responsive transcription in transiently transfected Caco2-BBE cells. Our results revealed that Sp1(−187), Sp1(−177), and the NF-κB binding site were essential for basal and IFN-γ-stimulated CD98 promoter activities, whereas Sp1(−874) and Sp1(−386) were not. The results from additional site-mutated CD98 promoters suggested that Sp1(−187), Sp1(−177), and the NF-κB site may cooperate in mediating basal and IFN-γ-stimulated CD98 promoter activities. Finally, we demonstrated that a reduction of Sp1 or NF-κB expression reduced CD98 protein expression in unstimulated and IFN-γ-stimulated Caco2-BBE cells. Collectively, these findings indicate that the Sp1 and NF-κB transcription factors are likely to play a significant role in IFN-γ-mediated transcriptional regulation of CD98 in the intestinal epithelium, providing new insights into the regulation of CD98 expression in intestinal inflammation.

Jak1 deficiency leads to enhanced Abelson-induced B-cell tumor formation

Blood ◽  
2003 ◽  
Vol 101 (12) ◽  
pp. 4937-4943 ◽  
Author(s):  
Veronika Sexl ◽  
Boris Kovacic ◽  
Roland Piekorz ◽  
Richard Moriggl ◽  
Dagmar Stoiber ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Interferon Γ ◽  
Tumor Formation ◽  
Scid Mice ◽  
Janus Kinase ◽  
Interferon Α ◽  
Ifn Γ ◽  
Transformed Cell Lines

AbstractThe Janus kinase Jak1 has been implicated in tumor formation by the Abelson oncogene. In this study we show that loss of Jak1 does not affect in vitro transformation by v-abl as defined by the ability to induce cytokine-independent B-cell colony formation or establishment of B-cell lines. However, Jak1-deficient, v-abl–transformed cell lines were more tumorgenic than wild-type cells when transplanted subcutaneously into severe combined immunodeficient (SCID) mice or injected intravenously into nude mice. Jak1 deficiency was associated with a loss in the ability of interferon-γ (IFN-γ)to induce growth arrest and/or apoptosis of v-abl–transformed pre-B cells or tumor growth in SCID mice. Moreover, IFN-γ mRNA could be detected in growing tumors, and tumor cells explanted from SCID mice had lost the ability to respond to IFN-γ in 9 of 20 cases, whereas the response to interferon-α (IFN-α) remained intact. Importantly, a similar increase in tumorgenicity was observed when IFN-γ–deficient cells were injected into SCID mice, identifying the tumor cell itself as the main source of IFN-γ. These findings demonstrate that Jak1, rather than promoting tumorgenesis as previously proposed, is critical in mediating an intrinsic IFN-γ–dependent tumor surveillance.

scholarly journals Reciprocal Protective Immunity againstBordetella pertussis and Bordetella parapertussis in a Murine Model of Respiratory Infection

2001 ◽  
Vol 69 (11) ◽  
pp. 6981-6986 ◽  
Author(s):  
Mineo Watanabe ◽  
Masaaki Nagai
Keyword(s):  
Immune Response ◽  
Respiratory Infection ◽  
Murine Model ◽  
Protective Immunity ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Spleen Cells ◽  
Bordetella Parapertussis ◽  
Ifn Γ

ABSTRACT The protective immunity induced by infection with Bordetella pertussis and with Bordetella parapertussis was examined in a murine model of respiratory infection. Convalescent mice that had been infected by aerosol with B. pertussis or with B. parapertussis exhibited a protective immune response against B. pertussis and also against B. parapertussis. Anti-filamentous hemagglutinin (anti-FHA) serum immunoglobulin G (IgG) and anti-FHA lung IgA antibodies were detected in both mice infected with B. pertussis and those infected with B. parapertussis. Antibodies against pertussis toxin (anti-PT) and against killed B. pertussis cells were detected in mice infected with B. pertussis. Pertactin-specific antibodies and antibodies against killed B. parapertussis cells were detected in mice infected with B. parapertussis. Spleen cells from mice infected with B. pertussis secreted interferon-γ (IFN-γ) in response to stimulation by FHA or PT. Spleen cells from mice infected with B. parapertussis also secreted IFN-γ in response to FHA. Interleukin-4 was not produced in response to any of the antigens tested. The profiles of cytokine secretion in vitro revealed induction of a Th1-biased immune response during convalescence from infection by B. pertussis and byB. parapertussis. It is possible that Th1 and Th2 responses against FHA might be related to the reciprocal protection achieved in our murine model.

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