scholarly journals NKG2D function protects the host from tumor initiation

2005 ◽  
Vol 202 (5) ◽  
pp. 583-588 ◽  
Author(s):  
Mark J. Smyth ◽  
Jeremy Swann ◽  
Erika Cretney ◽  
Nadeen Zerafa ◽  
Wayne M. Yokoyama ◽  
...  
Keyword(s):  
De Novo ◽  
Tumor Formation ◽  
Wild Type ◽  
Experimental Tumor ◽  
Host Protection ◽  
Ligand Expression ◽  
Ifn Γ ◽  
Deficient Mice ◽  
Nkg2d Receptor ◽  
Necrosis Factor

The activation NKG2D receptor has been shown to play an important role in the control of experimental tumor growth and metastases expressing ligands for NKG2D; however, a function for this recognition pathway in host protection from de novo tumorigenesis has never been demonstrated. We show that neutralization of NKG2D enhances the sensitivity of wild-type (WT) C57BL/6 and BALB/c mice to methylcholanthrene (MCA)-induced fibrosarcoma. The importance of the NKG2D pathway was additionally illustrated in mice deficient for either IFN-γ or tumor necrosis factor–related apoptosis-inducing ligand, whereas mice depleted of natural killer cells, T cells, or deficient for perforin did not display any detectable NKG2D phenotype. Furthermore, IL-12 therapy preventing MCA-induced sarcoma formation was also largely dependent on the NKG2D pathway. Although NKG2D ligand expression was variable or absent on sarcomas emerging in WT mice, sarcomas derived from perforin-deficient mice were Rae-1+ and immunogenic when transferred into WT syngeneic mice. These findings suggest an important early role for the NKG2D in controlling and shaping tumor formation.

IFN-γ deficiency attenuates hepatic inflammation and fibrosis in a steatohepatitis model induced by a methionine- and choline-deficient high-fat diet

2013 ◽  
Vol 305 (12) ◽  
pp. G891-G899 ◽  
Author(s):  
Xiao-Yu Luo ◽  
Terumi Takahara ◽  
Kengo Kawai ◽  
Masayuki Fujino ◽  
Toshiro Sugiyama ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Wild Type ◽  
High Fat ◽  
Tnf Α ◽  
Ifn Γ ◽  
Factor Α ◽  
Deficient Mice ◽  
Necrosis Factor

Cytokines play important roles in all stages of steatohepatitis, including hepatocyte injury, the inflammatory response, and the altered function of sinusoidal cells. This study examined the involvement of a major inflammatory cytokine, interferon-γ (IFN-γ), in the progression of steatohepatitis. In a steatohepatitis model by feeding a methionine- and choline-deficient high-fat (MCDHF) diet to both wild-type and IFN-γ-deficient mice, the liver histology, expression of genes encoding inflammatory cytokines, and fibrosis-related markers were examined. To analyze the effects of IFN-γ on Kupffer cells in vitro, we examined the tumor necrosis factor-α (TNF-α) production by a mouse macrophage cell line. Forty two days of MCDHF diet resulted in weight loss, elevated aminotransferases, liver steatosis, and inflammation in wild-type mice. However, the IFN-γ-deficient mice exhibited less extensive changes. RT-PCR revealed that the expression of tumor necrosis factor-α (TNF-α), transforming growth factor-β, inducible nitric oxide synthase, interleukin-4 and osteopontin were increased in wild-type mice, although they were suppressed in IFN-γ-deficient mice. Seventy days of MCDHF diet induced much more liver fibrosis in wild-type mice than in IFN-γ-deficient mice. The expression levels of fibrosis-related genes, α-smooth muscle actin, type I collagen, tissue inhibitor of matrix metalloproteinase-1, and matrix metalloproteinase-2, were dramatically increased in wild-type mice, whereas they were significantly suppressed in IFN-γ-deficient mice. Moreover, in vitro experiments showed that, when RAW 264.7 macrophages were treated with IFN-γ, they produced TNF-α in a dose-dependent manner. The present study showed that IFN-γ deficiency might inhibit the inflammatory response of macrophages cells and subsequently suppress stellate cell activation and liver fibrosis. These findings highlight the critical role of IFN-γ in the progression of steatohepatitis.

scholarly journals Toll-Like Receptor 2 Controls the Gamma Interferon Response to Francisella tularensis by Mouse Liver Lymphocytes

2007 ◽  
Vol 75 (11) ◽  
pp. 5338-5345 ◽  
Author(s):  
Kee-Jong Hong ◽  
Jason R. Wickstrum ◽  
Hung-Wen Yeh ◽  
Michael J. Parmely
Keyword(s):  
Francisella Tularensis ◽  
Cell Types ◽  
Gamma Interferon ◽  
Interferon Response ◽  
Interleukin 12 ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACT The production of gamma interferon (IFN-γ) is a key step in the protective innate immune response to Francisella tularensis. Natural killer cells and T cells in the liver are important sources of this cytokine during primary F. tularensis infections, and interleukin-12 (IL-12) appears to be an essential coactivating cytokine for hepatic IFN-γ expression. The present study was undertaken to determine whether or not macrophages (Mφ) or dendritic cells (DC) provide coactivating signals for the liver IFN-γ response in vitro, whether IL-12 mediates these effects, and whether Toll-like receptor (TLR) signaling is essential to induce this costimulatory activity. Both bone marrow-derived Mφ and DC significantly augmented the IFN-γ response of F. tularensis-challenged liver lymphocytes in vitro. While both cell types produced IL-12p40 in response to F. tularensis challenge, only DC secreted large quantities of IL-12p70. DC from both IL-12p35-deficient and TLR2-deficient mice failed to produce IL-12p70 and did not costimulate liver lymphocytes for IFN-γ production in response to viable F. tularensis organisms. Conversely, liver lymphocytes from TLR2-deficient mice cocultured with wild-type accessory cells produced IFN-γ at levels comparable to those for wild-type hepatic lymphocytes. These findings indicate that TLR2 controls hepatic lymphocyte IFN-γ responses to F. tularensis by regulating DC IL-12 production. While Mφ also coinduced hepatic IFN-γ production in response to F. tularensis, they did so in a fashion less dependent on TLR2.

scholarly journals Interleukin 10- and Fcγ Receptor-Deficient Mice Resolve Leishmania mexicana Lesions

2005 ◽  
Vol 73 (4) ◽  
pp. 2101-2108 ◽  
Author(s):  
Laurence U. Buxbaum ◽  
Phillip Scott
Keyword(s):  
Chronic Disease ◽  
Interleukin 10 ◽  
Delayed Type Hypersensitivity ◽  
Leishmania Mexicana ◽  
Wild Type ◽  
Enhanced Resistance ◽  
Lymph Node Cells ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACT Infection of C57BL/6 (B6) mice with Leishmania mexicana is associated with a minimal immune response and chronic disease. Here we show that B6 interleukin 10−/− (IL-10−/−) mice resolve their lesions and exhibit increased gamma interferon (IFN-γ), nitric oxide production, and delayed-type hypersensitivity. This enhanced resistance was dependent upon IL-12p40, since treatment of L. mexicana-infected IL-10−/− mice with anti-IL-12p40 monoclonal antibody abrogated healing. Antibody-opsonized L. mexicana induced IL-10 production by B6 macrophages in vitro, implicating antibody binding to Fc receptors as a mechanism involved in IL-10 production in this infection. Furthermore, B6 FcRγ−/− mice resolve L. mexicana lesions, and lymph node cells from these mice produced less IL-10 and more IFN-γ than cells from infected wild-type mice. These data demonstrate that removal of IL-10 or FcγR leads to resolution of L. mexicana disease and support a model in which ligation of FcγR by L. mexicana-bound immunoglobulin G promotes IL-10 production, leading to chronic disease.

scholarly journals CD8 T Cells Require Gamma Interferon To Clear Borna Disease Virus from the Brain and Prevent Immune System-Mediated Neuronal Damage

2005 ◽  
Vol 79 (21) ◽  
pp. 13509-13518 ◽  
Author(s):  
Jürgen Hausmann ◽  
Axel Pagenstecher ◽  
Karen Baur ◽  
Kirsten Richter ◽  
Hanns-Joachim Rziha ◽  
...  
Keyword(s):  
T Cells ◽  
Disease Virus ◽  
Cd8 T Cells ◽  
Gamma Interferon ◽  
Wild Type ◽  
Borna Disease Virus ◽  
Ifn Γ ◽  
The Brain ◽  
Deficient Mice ◽  
Borna Disease

ABSTRACT Borna disease virus (BDV) frequently causes meningoencephalitis and fatal neurological disease in young but not old mice of strain MRL. Disease does not result from the virus-induced destruction of infected neurons. Rather, it is mediated by H-2 k -restricted antiviral CD8 T cells that recognize a peptide derived from the BDV nucleoprotein N. Persistent BDV infection in mice is not spontaneously cleared. We report here that N-specific vaccination can protect wild-type MRL mice but not mutant MRL mice lacking gamma interferon (IFN-γ) from persistent infection with BDV. Furthermore, we observed a significant degree of resistance of old MRL mice to persistent BDV infection that depended on the presence of CD8 T cells. We found that virus initially infected hippocampal neurons around 2 weeks after intracerebral infection but was eventually cleared in most wild-type MRL mice. Unexpectedly, young as well as old IFN-γ-deficient MRL mice were completely susceptible to infection with BDV. Moreover, neurons in the CA1 region of the hippocampus were severely damaged in most diseased IFN-γ-deficient mice but not in wild-type mice. Furthermore, large numbers of eosinophils were present in the inflamed brains of IFN-γ-deficient mice but not in those of wild-type mice, presumably because of increased intracerebral synthesis of interleukin-13 and the chemokines CCL1 and CCL11, which can attract eosinophils. These results demonstrate that IFN-γ plays a central role in host resistance against infection of the central nervous system with BDV and in clearance of BDV from neurons. They further indicate that IFN-γ may function as a neuroprotective factor that can limit the loss of neurons in the course of antiviral immune responses in the brain.

Intraepithelial lymphocyte-derived interferon-γ evokes enterocyte apoptosis with parenteral nutrition in mice

2003 ◽  
Vol 284 (4) ◽  
pp. G629-G637 ◽  
Author(s):  
Hua Yang ◽  
Yongyi Fan ◽  
Daniel H. Teitelbaum
Keyword(s):  
Parenteral Nutrition ◽  
Fas Ligand ◽  
Interferon Γ ◽  
Intraepithelial Lymphocyte ◽  
Wild Type ◽  
Enterocyte Apoptosis ◽  
Resultant Increase ◽  
Ifn Γ ◽  
Fas L ◽  
Deficient Mice

Total parenteral nutrition (TPN) results in an increase in intraepithelial lymphocyte (IEL)-derived interferon-γ (IFN-γ) expression as well as an increase in epithelial cell (EC) apoptosis. This study examined the role that IEL-derived IFN-γ has in the increase in EC apoptosis. Mice received either TPN or oral feedings for 7 days. Small bowel EC apoptosis significantly rose in mice receiving TPN. The administration of TPN also significantly increased IEL-derived IFN-γ and Fas ligand (FasL) expression. EC apoptosis in IFN-γ knockout (IFNKO) mice that received TPN was significantly lower than in wild-type TPN mice. Sensitivity of EC to Fas-mediated apoptosis in IFNKO mice was significantly lower than in wild-type TPN mice. Apoptosis in Fas-deficient and FasL-deficient mice that received TPN was significantly lower than in wild-type mice that received TPN. The TPN-induced increase in IFN-γ expression appears to result in an increase in Fas-L expression and EC sensitivity to Fas, with a resultant increase in EC apoptosis. This may well be one of the mediators of increased EC apoptosis observed with TPN administration.

scholarly journals Distinct Roles of Lymphotoxin α and the Type I Tumor Necrosis Factor (TNF) Receptor in the Establishment of Follicular Dendritic Cells from Non–Bone Marrow–derived Cells

1997 ◽  
Vol 186 (12) ◽  
pp. 1997-2004 ◽  
Author(s):  
Mitsuru Matsumoto ◽  
Yang-Xin Fu ◽  
Hector Molina ◽  
Guangming Huang ◽  
Jinho Kim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Tumor Necrosis ◽  
Type I ◽  
Follicular Dendritic Cells ◽  
Wild Type ◽  
Lymphotoxin Α ◽  
Deficient Mice ◽  
Necrosis Factor

In mice deficient in either lymphotoxin α (LT-α) or type I tumor necrosis factor receptor (TNFR-I), organized clusters of follicular dendritic cells (FDC) and germinal centers (GC) are absent from the spleen. We investigated the role of LT-α and TNFR-I in the establishment of spleen FDC and GC structure by using reciprocal bone marrow (BM) transfer. When LT-α–deficient mice were reconstituted with wild-type BM, FDC organization and the ability to form GC were restored, indicating that the LT-α–expressing cells required to establish organized FDC are derived from BM. The role of LT-α in establishing organized FDC structure was further investigated by the transfer of complement receptor 1 and 2 (CR1/2)–deficient BM cells into LT-α–deficient mice. Organized FDC were identified with both the FDC-M1 and anti-CR1 monoclonal antibodies in these BM-chimeric mice, indicating that these cells were derived from the LT-α–deficient recipient. Thus, expression of LT-α in the BM-derived cells, but not in the non–BM-derived cells, is required for the maturation of FDC from non-BM precursor cells. In contrast, when TNFR-I–deficient mice were reconstituted with wild-type BM, they showed no detectable FDC clusters or GC formation. This indicates that TNFR-I expression on non–BM-derived cellular components is necessary for the establishment of these lymphoid structures. TNFR-I–deficient BM was able to restore FDC organization and GC formation in LT-α–deficient mice, indicating that formation of these structures does not require TNFR-I expression on BM-derived cells. The data in this study demonstrate that FDC organization and GC formation are controlled by both LT-α–expressing BM-derived cells and by TNFR-I-expressing non–BM-derived cells.

scholarly journals Migration-Inhibitory Factor Gene-Deficient Mice Are Susceptible to Cutaneous Leishmania major Infection

2001 ◽  
Vol 69 (2) ◽  
pp. 906-911 ◽  
Author(s):  
Abhay R. Satoskar ◽  
Marcelo Bozza ◽  
Miriam Rodriguez Sosa ◽  
Guoshing Lin ◽  
John R. David
Keyword(s):  
Migration Inhibitory Factor ◽  
Protective Immunity ◽  
Leishmania Major ◽  
Inhibitory Factor ◽  
Interleukin 4 ◽  
Wild Type ◽  
Leishmanicidal Activity ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACT To determine the role of endogenous migration-inhibitory factor (MIF) in the development of protective immunity against cutaneous leishmaniasis, we analyzed the course of cutaneous Leishmania major infection in MIF gene-deficient mice (MIF−/−) and wild-type (MIF+/+) mice. Following cutaneous L. major infection, MIF−/− mice were susceptible to disease and developed significantly larger lesions and greater parasite burdens than MIF+/+ mice. Interestingly, antigen-stimulated lymph node cells from MIF−/− mice produced more interleukin-4 (IL-4) and gamma interferon (IFN-γ) than those from MIF+/+ mice, although the differences were statistically not significant. IFN-γ-activated resting peritoneal macrophages from MIF−/− mice showed impaired macrophage leishmanicidal activity and produced significantly lower levels of nitric oxide and superoxide in vitro. The macrophages from MIF−/− mice, however, produced much more IL-6 than macrophages from wild-type mice. These findings demonstrate that endogenous MIF plays an important role in the development of protective immunity against L. majorin vivo. Furthermore, they indicate that the susceptibility of MIF−/− mice to L. major infection is due to impaired macrophage leishmanicidal activity rather than dysregulation of Th1 and Th2 responses.

scholarly journals Destructive Arthritis in Vaccinated Interferon Gamma-Deficient Mice Challenged with Borrelia burgdorferi: Modulation by Tumor Necrosis Factor Alpha

2003 ◽  
Vol 10 (1) ◽  
pp. 44-52 ◽  
Author(s):  
John A. Christopherson ◽  
Erik L. Munson ◽  
Douglas M. England ◽  
Cindy L. Croke ◽  
Monica C. Remington ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Borrelia Burgdorferi ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Ifn Γ ◽  
Deficient Mice ◽  
Necrosis Factor

ABSTRACT We found that Borrelia burgdorferi-vaccinated gamma interferon-deficient (IFN-γ0) mice challenged with B. burgdorferi developed prominent chronic destructive osteoarthropathy. When these mice were treated with anti-tumor necrosis factor alpha (TNF-α) antibody, the severity of the destructive osteoarthritis was enhanced and affected the mobility of the animals. In addition, extensive swelling of the hind paws occurred. In contrast, treatment of B. burgdorferi-vaccinated, challenged IFN-γ0 mice with recombinant TNF-α (rTNF-α) inhibited the development of arthritis, including swelling of the hind paws. Moreover, treatment of vaccinated, challenged IFN-γ0 mice with anti-TNF-α inhibited fourfold the production of an antibody that kills B. burgdorferi, while treatment of vaccinated, challenged IFN-γ0 mice with rTNF-α slightly elevated the level of the borreliacidal antibody. These results suggest that the level of TNF-α directly or indirectly regulates the production of borreliacidal antibody and the development of vaccine-induced destructive Lyme osteoarthritis. Studies are in progress to determine the mechanism by which TNF-α-dependent cytokines generate the destructive arthritis.

Contrasting roles for STAT4 and STAT6 signal transduction pathways in murine renal ischemia-reperfusion injury

2003 ◽  
Vol 285 (2) ◽  
pp. F319-F325 ◽  
Author(s):  
Naoko Yokota ◽  
Melissa Burne-Taney ◽  
Lorraine Racusen ◽  
Hamid Rabb
Keyword(s):  
T Cells ◽  
Reperfusion Injury ◽  
Cd4 T Cells ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Wild Type ◽  
Renal Ischemia Reperfusion Injury ◽  
Ifn Γ ◽  
Deficient Mice

Recent data support a modulatory role for CD4 T cells in experimental renal ischemia-reperfusion injury (IRI). CD4 T cells can functionally differentiate to either a Th1 (IFN-γ producing) or the counterbalancing Th2 (IL-4) phenotype. The enzymes signal transducers and activators of transcription (STAT) 4 and STAT6 regulate Th1 or Th2 differentiation and cytokine production, respectively. We therefore hypothesized that mice that were STAT4 deficient would be protected from renal IRI and that STAT6-deficient mice would have a more severe course. Intracellular cytokine staining of splenocytes from STAT4–/– or STAT6–/– exhibited distinct IFN-γ and IL-4 cytokine expression profiles. STAT6–/– had markedly worse renal function and tubular injury postischemia compared with wild type. STAT4–/– had only mildly improved function. Renal phagocyte infiltration and ICAM-1 upregulation were similar in STAT4–/–, STAT6–/–, and wild type. To evaluate if the mechanism of the marked worsening in the STAT6–/– mice could be due to IL-4 deficiency, IL-4-deficient mice were studied and had similar postischemic phenotype to STAT6–/– mice. These data demonstrate that the STAT6 pathway has a major protective role in renal IRI. IL-4 deficiency is a likely mechanism underlying the STAT6 effect. A “yin-yang” role for inflammation is emerging in renal IRI, similar to recent observations in atherosclerosis.

scholarly journals Gamma Interferon-Induced Inhibition ofToxoplasma gondii in Astrocytes Is Mediated by IGTP

2001 ◽  
Vol 69 (9) ◽  
pp. 5573-5576 ◽  
Author(s):  
Sandra K. Halonen ◽  
Gregory A. Taylor ◽  
Louis M. Weiss
Keyword(s):  
Immunoblot Analysis ◽  
Significant Inhibition ◽  
Gamma Interferon ◽  
Wild Type ◽  
Effector Cells ◽  
Inhibition Of Growth ◽  
The Central Nervous System ◽  
Ifn Γ ◽  
The Brain ◽  
Deficient Mice

ABSTRACT Toxoplasma gondii is an important pathogen in the central nervous system, causing a severe and often fatal encephalitis in patients with AIDS. Gamma interferon (IFN-γ) is the main cytokine preventing reactivation of Toxoplasma encephalitis in the brain. Microglia are important IFN-γ-activated effector cells controlling the growth of T. gondii in the brain via a nitric oxide (NO)-mediated mechanism. IFN-γ can also activate astrocytes to inhibit the growth of T. gondii. Previous studies found that the mechanism in murine astrocytes is independent of NO and all other known anti-Toxoplasma mechanisms. In this study we investigated the role of IGTP, a recently identified IFN-γ-regulated gene, in IFN-γ inhibition of T. gondii in murine astrocytes. Primary astrocytes were cultivated from IGTP-deficient mice, treated with IFN-γ, and then tested for anti-Toxoplasma activity. In wild-type astrocytesT. gondii growth was significantly inhibited by IFN-γ, whereas in astrocytes from IGTP-deficient mice IFN-γ did not cause a significant inhibition of growth. Immunoblot analysis confirmed that IFN-γ induced significant levels of IGTP in wild-type murine astrocytes within 24 h. These results indicate that IGTP plays a central role in the IFN-γ-induced inhibition of T. gondii in murine astrocytes.

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