Improved superoxide-generating ability by interferon γ due to splicing pattern change of transcripts in neutrophils from patients with a splice site mutation inCYBB gene

Blood ◽  
2001 ◽  
Vol 98 (2) ◽  
pp. 436-441 ◽  
Author(s):  
Fuminari Ishibashi ◽  
Tomoyuki Mizukami ◽  
Shiro Kanegasaki ◽  
Lena Motoda ◽  
Ryota Kakinuma ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Present Report ◽  
Interferon Γ ◽  
Silent Mutation ◽  
Site Mutation ◽  
Splicing Pattern ◽  
Cybb Gene ◽  
Gene Transcripts ◽  
Ifn Γ ◽  
Neutrophil Superoxide

Chronic granulomatous disease (CGD) is an inherited disorder of host defense against microbial infections caused by defective activity of the phagocyte NADPH oxidase. Based on an increase of neutrophil superoxide-generating ability in response to interferon γ (IFN-γ) in a single patient with CGD, multicentered group studies demonstrated a beneficial effect of prophylactic IFN-γ. However, no apparent increase of the phagocyte superoxide generation was found in patients enrolled in these studies. The present report offers an additional kindred in whom an IFN-γ–dependent increase in neutrophil superoxide production was observed in 3 affected patients. The defect in the CYBB gene for gp91-phox was identified as an otherwise silent mutation adjacent to the third intron of theCYBB gene that alters messenger RNA splicing. By molecular analysis, significant differences were found in the splicing pattern ofCYBB gene transcripts in patient neutrophils between 1 and 25 days after administration of IFN-γ. Furthermore, a complete transcript containing the missing exons could be detected in all specimens after the treatment. The changes in the splicing pattern of the transcripts and the prolonged effect on superoxide-generating ability of patient neutrophils indicate that IFN-γ induced a partial correction of the abnormal splicing of CYBB gene transcripts in myeloid progenitor cells.

scholarly journals Deacetylation of p53 induces autophagy by suppressing Bmf expression

2013 ◽  
Vol 201 (3) ◽  
pp. 427-437 ◽  
Author(s):  
Amelia U. Contreras ◽  
Yohannes Mebratu ◽  
Monica Delgado ◽  
Gilbert Montano ◽  
Chien-an A. Hu ◽  
...  
Keyword(s):  
Cell Death ◽  
Messenger Rna ◽  
Histone Deacetylase Inhibitors ◽  
Interferon Γ ◽  
Airway Epithelial Cells ◽  
Dependent Manner ◽  
Airway Epithelial ◽  
Independent Manner ◽  
Rich Domain ◽  
Ifn Γ

Interferon γ (IFN-γ)–induced cell death is mediated by the BH3-only domain protein, Bik, in a p53-independent manner. However, the effect of IFN-γ on p53 and how this affects autophagy have not been reported. The present study demonstrates that IFN-γ down-regulated expression of the BH3 domain-only protein, Bmf, in human and mouse airway epithelial cells in a p53-dependent manner. p53 also suppressed Bmf expression in response to other cell death–stimulating agents, including ultraviolet radiation and histone deacetylase inhibitors. IFN-γ did not affect Bmf messenger RNA half-life but increased nuclear p53 levels and the interaction of p53 with the Bmf promoter. IFN-γ–induced interaction of HDAC1 and p53 resulted in the deacetylation of p53 and suppression of Bmf expression independent of p53’s proline-rich domain. Suppression of Bmf facilitated IFN-γ–induced autophagy by reducing the interaction of Beclin-1 and Bcl-2. Furthermore, autophagy was prominent in cultured bmf−/− but not in bmf+/+ cells. Collectively, these observations show that deacetylation of p53 suppresses Bmf expression and facilitates autophagy.

scholarly journals Interleukin-6 Overcomes p21WAF1 Upregulation and G1 Growth Arrest Induced by Dexamethasone and Interferon-γ in Multiple Myeloma Cells

Blood ◽  
1997 ◽  
Vol 90 (1) ◽  
pp. 279-289 ◽  
Author(s):  
Mitsuyoshi Urashima ◽  
Gerrard Teoh ◽  
Dharminder Chauhan ◽  
Yasutaka Hoshi ◽  
Atsushi Ogata ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Protein Expression ◽  
Interleukin 6 ◽  
Present Report ◽  
Growth Arrest ◽  
Interferon Γ ◽  
Cell Cycle Distribution ◽  
P21 Protein ◽  
Ifn Γ

Abstract Interleukin-6 (IL-6) is a growth factor for multiple myeloma (MM) cells and can inhibit MM cell apoptosis. Our recent studies show that IL-6 facilitates MM cell growth via phosphorylation of retinoblastoma protein (pRB); however, the effects of IL-6 on those cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors (CDIs) that are known to regulate phosphorylation of pRB have not been defined in MM cells. In the present report, we cultured MM cell lines and patient cells with IL-6 and/or dexamethasone (Dex) and characterized changes in cell cycle; expression and association of cyclins, CDKs, and CDIs; and phosphorylation of pRB. Dex induced G1 growth arrest in MM cells, whereas IL-6 facilitated G1 to S phase transition; moreover, the effect of Dex was blocked by IL-6. p21WAF1 (p21) protein was constitutively expressed in the majority of MM cells independent of the status of p53. Its expression was upregulated by Dex and downregulated by IL-6; again, IL-6 inhibited the increase in p21 triggered by Dex. These alterations in p21 expression in MM cells were associated with changes in p21 binding to CDK2, CDK4, and CDK6; CDK2, CDK4, and CDK6 kinase activities; and phosphorylation of pRB. In contrast, expression of G1 cell cycle regulatory proteins, including p27KIP1, cyclin D2, and cyclin E, was not altered in MM cells cultured with Dex and/or IL-6. Finally, interferon-γ (IFN-γ) also induced G1 growth arrest and upregulated p21 protein expression; as with Dex, affects of IFN-γ were inhibited by IL-6. Our results therefore show that changes in cell cycle distribution in MM cells triggered by Dex, IL-6, and IFN-γ correlate with changes in p21 protein expression and implicate p21 in the coupling of Dex-, IL-6–, and IFN-γ–related signals to G1 cell cycle regulation in MM cells.

scholarly journals Interleukin-6 Overcomes p21WAF1 Upregulation and G1 Growth Arrest Induced by Dexamethasone and Interferon-γ in Multiple Myeloma Cells

Blood ◽  
1997 ◽  
Vol 90 (1) ◽  
pp. 279-289 ◽  
Author(s):  
Mitsuyoshi Urashima ◽  
Gerrard Teoh ◽  
Dharminder Chauhan ◽  
Yasutaka Hoshi ◽  
Atsushi Ogata ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Protein Expression ◽  
Interleukin 6 ◽  
Present Report ◽  
Growth Arrest ◽  
Interferon Γ ◽  
Cell Cycle Distribution ◽  
P21 Protein ◽  
Ifn Γ

Interleukin-6 (IL-6) is a growth factor for multiple myeloma (MM) cells and can inhibit MM cell apoptosis. Our recent studies show that IL-6 facilitates MM cell growth via phosphorylation of retinoblastoma protein (pRB); however, the effects of IL-6 on those cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors (CDIs) that are known to regulate phosphorylation of pRB have not been defined in MM cells. In the present report, we cultured MM cell lines and patient cells with IL-6 and/or dexamethasone (Dex) and characterized changes in cell cycle; expression and association of cyclins, CDKs, and CDIs; and phosphorylation of pRB. Dex induced G1 growth arrest in MM cells, whereas IL-6 facilitated G1 to S phase transition; moreover, the effect of Dex was blocked by IL-6. p21WAF1 (p21) protein was constitutively expressed in the majority of MM cells independent of the status of p53. Its expression was upregulated by Dex and downregulated by IL-6; again, IL-6 inhibited the increase in p21 triggered by Dex. These alterations in p21 expression in MM cells were associated with changes in p21 binding to CDK2, CDK4, and CDK6; CDK2, CDK4, and CDK6 kinase activities; and phosphorylation of pRB. In contrast, expression of G1 cell cycle regulatory proteins, including p27KIP1, cyclin D2, and cyclin E, was not altered in MM cells cultured with Dex and/or IL-6. Finally, interferon-γ (IFN-γ) also induced G1 growth arrest and upregulated p21 protein expression; as with Dex, affects of IFN-γ were inhibited by IL-6. Our results therefore show that changes in cell cycle distribution in MM cells triggered by Dex, IL-6, and IFN-γ correlate with changes in p21 protein expression and implicate p21 in the coupling of Dex-, IL-6–, and IFN-γ–related signals to G1 cell cycle regulation in MM cells.

scholarly journals Natural History and Evolution of Anti-Interferon-γ Autoantibody-Associated Immunodeficiency Syndrome in Thailand and the United States

2019 ◽  
Vol 71 (1) ◽  
pp. 53-62 ◽  
Author(s):  
Gloria H Hong ◽  
Ana M Ortega-Villa ◽  
Sally Hunsberger ◽  
Ploenchan Chetchotisakd ◽  
Siriluck Anunnatsiri ◽  
...  
Keyword(s):  
United States ◽  
Natural History ◽  
The United States ◽  
Interferon Γ ◽  
Mycobacterium Abscessus ◽  
Annual Data ◽  
Persistent Infections ◽  
Ifn Γ ◽  
Immunodeficiency Syndrome

Abstract Background The natural history of anti-interferon-γ (IFN-γ) autoantibody-associated immunodeficiency syndrome is not well understood. Methods Data of 74 patients with anti-IFN-γ autoantibodies at Srinagarind Hospital, Thailand, were collected annually (median follow-up duration, 7.5 years). Annual data for 19 patients and initial data for 4 patients with anti-IFN-γ autoantibodies at the US National Institutes of Health were collected (median follow-up duration, 4.5 years). Anti-IFN-γ autoantibody levels were measured in plasma samples. Results Ninety-one percent of US patients were of Southeast Asian descent; there was a stronger female predominance (91%) in US than Thai (64%) patients. Mycobacterium abscessus (34%) and Mycobacterium avium complex (83%) were the most common nontuberculous mycobacteria in Thailand and the United States, respectively. Skin infections were more common in Thailand (P = .001), whereas bone (P < .0001), lung (P = .002), and central nervous system (P = .03) infections were more common in the United States. Twenty-four percent of Thai patients died, most from infections. None of the 19 US patients with follow-up data died. Anti-IFN-γ autoantibody levels decreased over time in Thailand (P < .001) and the United States (P = .017), with either cyclophosphamide (P = .01) or rituximab therapy (P = .001). Conclusions Patients with anti-IFN-γ autoantibodies in Thailand and the United States had distinct demographic and clinical features. While titers generally decreased with time, anti-IFN-γ autoantibody disease had a chronic clinical course with persistent infections and death. Close long-term surveillance for new infections is recommended.

scholarly journals The Role of Interleukine-10 and Interferon-γ as Potential Markers of the Evolution of African Swine Fever Virus Infection in Wild Boar

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 757
Author(s):  
Sandra Barroso-Arévalo ◽  
Jose A. Barasona ◽  
Estefanía Cadenas-Fernández ◽  
José M. Sánchez-Vizcaíno
Keyword(s):  
Wild Boar ◽  
Vaccine Candidate ◽  
African Swine Fever Virus ◽  
African Swine Fever ◽  
Interferon Γ ◽  
Fever Virus ◽  
Control Group ◽  
Challenge Virus ◽  
Ifn Γ

African swine fever virus (ASFv) is one of the most challenging pathogens to affect both domestic and wild pigs. The disease has now spread to Europe and Asia, causing great damage to the pig industry. Although no commercial vaccine with which to control the disease is, as yet, available, some potential vaccine candidates have shown good results in terms of protection. However, little is known about the host immune mechanisms underlying that protection, especially in wild boar, which is the main reservoir of the disease in Europe. Here, we study the role played by two cytokines (IL-10 and IFN-γ) in wild boar orally inoculated with the attenuated vaccine candidate Lv17/WB/Rie1 and challenged with a virulent ASFv genotype II isolate. A group of naïve wild boar challenged with the latter isolate was also established as a control group. Our results showed that both cytokines play a key role in protecting the host against the challenge virus. While high levels of IL-10 in serum may trigger an immune system malfunctioning in challenged animals, the provision of stable levels of this cytokine over time may help to control the disease. This, together with high and timely induction of IFN-γ by the vaccine candidate, could help protect animals from fatal outcomes. Further studies should be conducted in order to support these preliminary results and confirm the role of these two cytokines as potential markers of the evolution of ASFV infection.

scholarly journals THU0052 RELATIONSHIP BETWEEN INTERFERON-Γ-PRODUCING IMMUNOCOMPETENT CELLS AND DISEASE ACTIVITY IN ADULT-ONSET STILL’S DISEASE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 238.1-238
Author(s):  
Y. Shimojima ◽  
D. Kishida ◽  
T. Ichikawa ◽  
Y. Sekijima
Keyword(s):  
T Cells ◽  
Disease Activity ◽  
Nk Cells ◽  
Acute Phase ◽  
Serum Ferritin ◽  
Interferon Γ ◽  
Adult Onset Still’S Disease ◽  
Still’S Disease ◽  
Ifn Γ ◽  
Adult Onset Still's Disease

Background:In the acute phase of adult-onset Still’s disease (AOSD), elevated levels of proinflammatory cytokines including interferon-γ (IFN-γ) are shown. Moreover, IFN-γ impacts on activating macrophages which play a crucial role in the pathogenesis of AOSD. Natural killer (NK) cells and T helper cells are in charge of secreting IFN-γ in the innate and adaptive immune systems of disease, respectively. However, the features of their IFN-γ-producing variation depending on disease activity are still uncertain in AOSD.Objectives:We investigated characteristics of IFN-γ-producing CD4+T cells and NK cells in patients with AOSD.Methods:Twenty-four patients in the acute phase of AOSD (active AOSD), 8 of them after treatment (remission), and 12 healthy controls (HC) were recruited in this study. Peripheral blood mononuclear cells and serum samples were provided from them for the experimental analysis. Flow cytometry was used for analyzing CD4+T cells, CD4+regulatory T cells (Tregs), NK cells, and their intracellular IFN-γ expression levels as well as suppression assay of Tregs. The serum concentration of interleukin-18 (IL-18) was measured using commercially available ELISA kit. Relationship between the analyzed data and clinical findings related to disease activity were statistically evaluated.Results:IFN-γ expression in CD4+T cells was significantly higher in active AOSD than in HC (p < 0.05). Tregs also significantly indicated higher expression of IFN-γ in active AOSD than in HC (p < 0.0001); and moreover, Tregs were significantly impaired in their suppression ability (p < 0.05). In both CD4+T cells and Tregs, expression of IFN-γ was significantly correlated with serum ferritin levels in active AOSD (p < 0.05). IFN-γ expression in CD4+T cells was significantly higher in patients with splenomegaly than those without that (p < 0.05). The proportion of NK cells was significantly lower in active AOSD than in HC (p < 0.005), whereas IFN-γ expression in NK cells was significantly higher in active AOSD than in HC (p < 0.0005). The number of NK cells and IFN-γ-expressing NK cells had inverse relationship with serum ferritin levels in active AOSD (p < 0.05 and p < 0.005, respectively). Increased number of NK cells and their decreased expression of IFN-γ were significantly demonstrated in remission (p < 0.05). In the analyses of NK cell subsets, lower expression of IFN-γ in CD56brightNK cells and higher that in CD56dimNK cells were significantly indicated in active AOSD than HC (p < 0.05). In remission, IFN-γ expression was significantly decreased in CD56dimNK cells (p < 0.05) despite no significant recovery of that in CD56brightNK cells (p = 0.311). Meanwhile, increased expression of IFN-γ in CD56brightNK cells was demonstrated in only patients who were treated with biologics. Although serum levels of IL-18 were significantly higher in active AOSD than in remission and HC; however, they had no significant correlations with any analyzed data.Conclusion:CD4+T cells and NK cells promote IFN-γ expression in the acute phase of AOSD. Meanwhile, increased expression of IFN-γ in CD4+T cells and decreased number of NK cells were correlated with serum ferritin levels, suggesting that they are indicators of disease activity. Furthermore, high disease activity may impact on the alteration of IFN-γ-producing balance in two distinct population of NK cells, and the plasticity of Tregs leading to defect in suppression ability.Disclosure of Interests:None declared

Regulation of mouse natural killer (NK) activity by interferon-γ (IFN-γ)

1985 ◽  
Vol 7 (3) ◽  
pp. 327
Author(s):  
F. Velotti ◽  
A. Santoni ◽  
F. Cofano ◽  
S. Landolfo ◽  
M. Piccoli ◽  
...  
Keyword(s):  
Natural Killer ◽  
Interferon Γ ◽  
Nk Activity ◽  
Ifn Γ

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.

Messenger RNA in Dormant Cells of Sterkiella histriomuscorum (Oxytrichidae): Identification of Putative Regulatory Gene Transcripts

Protist ◽  
1999 ◽  
Vol 150 (2) ◽  
pp. 137-147 ◽  
Author(s):  
Anne Baroin Tourancheau ◽  
Loic Morin ◽  
Tie Yang ◽  
Roland Perasso
Keyword(s):  
Messenger Rna ◽  
Regulatory Gene ◽  
Dormant Cells ◽  
Gene Transcripts

scholarly journals Differential Regulation of Cathepsin S and Cathepsin L in Interferon γ–treated Macrophages

2003 ◽  
Vol 197 (2) ◽  
pp. 169-179 ◽  
Author(s):  
Courtney Beers ◽  
Karen Honey ◽  
Susan Fink ◽  
Katherine Forbush ◽  
Alexander Rudensky
Keyword(s):  
Cathepsin L ◽  
Specific Inhibitor ◽  
Cell Types ◽  
Interferon Γ ◽  
Cathepsin S ◽  
Antigen Presenting Cell ◽  
Relative Contribution ◽  
Helper Cell Type ◽  
Ifn Γ ◽  
Antigen Presenting

Cathepsin S (catS) and cathepsin L (catL) mediate late stages of invariant chain (Ii) degradation in discrete antigen-presenting cell types. Macrophages (Mϕs) are unique in that they express both proteases and here we sought to determine the relative contribution of each enzyme. We observe that catL plays no significant role in Ii cleavage in interferon (IFN)-γ–stimulated Mϕs. In addition, our studies show that the level of catL activity is significantly decreased in Mϕs cultured in the presence of IFN-γ whereas catS activity increases. The decrease in catL activity upon cytokine treatment occurs despite the persistence of high levels of mature catL protein, suggesting that a specific inhibitor of the enzyme is up-regulated in IFN-γ–stimulated peritoneal Mϕs. Similar inhibition of activity is observed in dendritic cells engineered to overexpress catL. Such enzymatic inhibition in Mϕs exhibits only partial dependence upon Ii and therefore, other mechanisms of catL inhibition are regulated by IFN-γ. Thus, during a T helper cell type 1 immune response catL inhibition in Mϕs results in preferential usage of catS, such that major histocompatibility complex class II presentation by all bone marrow–derived antigen-presenting cell is regulated by catS.

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