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 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 FcγRIII Mediates Immunoglobulin G-Induced Interleukin-10 and Is Required for Chronic Leishmania mexicana Lesions

2007 ◽  
Vol 76 (2) ◽  
pp. 623-631 ◽  
Author(s):  
Bolaji N. Thomas ◽  
Laurence U. Buxbaum
Keyword(s):  
Chronic Disease ◽  
T Cell Receptors ◽  
Protective Immunity ◽  
Interleukin 10 ◽  
Parasite Infection ◽  
Interferon Response ◽  
Parasite Control ◽  
Leishmania Mexicana ◽  
Wild Type ◽  
Specific Igg

ABSTRACT FcRγ and interleukin-10 (IL-10) are both required for chronic disease in C57BL/6 mice with Leishmania mexicana parasite infection. FcRγ is a component of several different FcRs and may be a component of some T-cell receptors. The initial antibody response to L. mexicana is an immunoglobulin G1 (IgG1) response, and IgG1 preferentially binds to FcγRIII in other systems. To begin to dissect the mechanisms by which FcγRs contribute to chronic disease, we infected FcγRIII knockout (KO) mice with L. mexicana. We show that FcγRIII KO mice are resistant to L. mexicana infection, resolving lesions in association with a stronger gamma interferon response, similar to IL-10 KO mice, with parasite control by 12 weeks. We found that the Leishmania-specific IgG response is unaltered in FcγRIII KO mice compared with that in wild-type controls. The frequencies of IL-10 production from lymph node CD25+ CD4+ T cells are the same in KO and wild-type mice, and depletion of CD25+ cells did not alter the course of infection, implying that Treg cells may not be the mechanism for susceptibility to L. mexicana infection, unlike for L. major infection. However, IL-10 mRNA was greatly diminished in the lesions of FcγRIII KO mice compared to that of B6 controls. Furthermore, macrophages from FcγRIII KO and FcRγ KO mice have the same profound defect in IL-10 production induced by IgG-opsonized amastigotes. We also found IL-10-dependent (major) and -independent (minor) inhibition of IL-12 mediated by FcγRIII, as well as parasite-mediated inhibition of IL-12 and induction of IL-10, independent of FcγR. Our data demonstrate a specific role for FcγRIII in suppressing protective immunity in L. mexicana infection, likely through macrophage IL-10 production in the lesion.

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 Interleukin-10 from T Cells, but Not Macrophages and Granulocytes, Is Required for Chronic Disease in Leishmania mexicana Infection

2015 ◽  
Vol 83 (4) ◽  
pp. 1366-1371 ◽  
Author(s):  
Laurence U. Buxbaum
Keyword(s):  
T Cells ◽  
Chronic Disease ◽  
Indirect Evidence ◽  
Protozoan Parasite ◽  
Interleukin 10 ◽  
Parasite Control ◽  
Leishmania Mexicana ◽  
Wild Type ◽  
Indirect Pathway ◽  
Content Type

Chronic cutaneous disease of mice caused by the protozoan parasiteLeishmania mexicanarequires interleukin-10 (IL-10) and FcγRIII (an activating IgG receptor). Macrophages readily secrete IL-10 in response to IgG-coated amastigotes, making macrophages a prime candidate as the critical source of IL-10. However, indirect evidence suggested that macrophage IL-10 is not essential for chronic disease. I now show directly that mice lacking IL-10 from macrophages and granulocytes still have chronic disease, like wild-type C57BL/6 mice. However, T cell-derived IL-10 is required for chronic disease. CD4-cre IL-10flox/floxmice lack IL-10 from T cells (both CD4+and CD8+) and heal theirL. mexicanalesions, with parasite control. I had previously shown that depletion of CD25+T cells had no effect on chronic disease, and thus, T cells other than CD25+regulatory T (Treg) cells should be the important source of IL-10. Given that conventional T cells do not express FcγRs, there is likely to be an indirect pathway by which FcγRIII on some other cell engaged by IgG1-amastigote immune complexes induces IL-10 from T cells. Further work is needed to delineate these pathways.

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 Interleukin-10 Is a Natural Suppressor of Cytokine Production and Inflammation in a Murine Model of Allergic Bronchopulmonary Aspergillosis

1997 ◽  
Vol 185 (6) ◽  
pp. 1089-1100 ◽  
Author(s):  
Gabriele Grünig ◽  
David B. Corry ◽  
Michael W. Leach ◽  
Brian W.P. Seymour ◽  
Viswanath P. Kurup ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Gene Knockout ◽  
Allergic Bronchopulmonary Aspergillosis ◽  
Interleukin 10 ◽  
Lung Cells ◽  
Wild Type ◽  
Outbred Mice ◽  
Ifn Γ

We have used interleukin-10 (IL-10) gene knockout mice (IL-10−/−) to examine the role of endogenous IL-10 in allergic lung responses to Aspergillus fumigatus Ag. In vitro restimulated lung cells from sensitized IL-10−/− mice produced exaggerated amounts of IL-4, IL-5, and interferon-γ (IFN-γ) compared with wild-type (WT) lung cells. In vivo, the significance of IL-10 in regulating responses to repeated A. fumigatus inhalation was strikingly revealed in IL-10−/− outbred mice that had a 50–60% mortality rate, while mortality was rare in similarly treated WT mice. Furthermore, IL-10−/− outbred mice exhibited exaggerated airway inflammation and heightened levels of IL-5 and IFN-γ in bronchoalveolar lavage (BAL) fluids. In contrast, the magnitude of the allergic lung response was similar in intranasally (i.n.) sensitized IL-10−/− and wild-type mice from a different strain (C57BL/6). Using a different route of priming (intraperitoneal) followed by one i.n. challenge we found that IL-10−/− C57BL/6 mice had heightened eosinophilic airway inflammation, BAL–IL-5 levels, and numbers of αβT cells in the lung tissues compared with WT mice. We conclude that IL-10 can suppress inflammatory Th2-like lung responses as well as Th1-like responses given the constraints of genetic background and route of priming.

Vascular interleukin-10 protects against LPS-induced vasomotor dysfunction

2005 ◽  
Vol 289 (2) ◽  
pp. H624-H630 ◽  
Author(s):  
Carol A. Gunnett ◽  
Donald D. Lund ◽  
Frank M. Faraci ◽  
Donald D. Heistad
Keyword(s):  
Gene Transfer ◽  
Vascular Dysfunction ◽  
Interleukin 10 ◽  
Wild Type ◽  
Low Concentration ◽  
Adenoviral Gene Transfer ◽  
Vasomotor Dysfunction ◽  
Deficient Mice

We tested the hypotheses that 1) systemic IL-10, after adenoviral gene transfer, protects arteries from impaired relaxation produced by LPS; 2) local expression of IL-10 within the arterial wall protects against vasomotor dysfunction after LPS; and 3) IL-10 protects against vascular dysfunction mediated by inducible NO synthase (iNOS) after LPS. In IL-10-deficient (IL-10−/−) and wild-type (WT, IL-10+/+) mice, LPS in vivo impaired relaxation of arteries to acetylcholine and gene transfer of IL-10 improved responses to acetylcholine. Superoxide levels were elevated in arteries after LPS, and increased levels of superoxide were prevented by gene transfer of IL-10. In arteries incubated with a low concentration of LPS in vitro to eliminate systemic effects of LPS and IL-10 from nonvascular sources, responses to acetylcholine were impaired in IL-10-deficient mice and impairment was largely prevented by gene transfer in vitro of IL-10. In arteries from WT mice in vitro, the low concentration of LPS did not impair responses to acetylcholine. Thus IL-10 within the vessel wall protects against LPS-induced dysfunction. In IL-10-deficient mice, aminoguanidine, which inhibits iNOS, protected against vasomotor dysfunction after LPS. In arteries from iNOS-deficient mice, LPS did not impair responses to acetylcholine. These findings suggest that both systemic and local effects of IL-10 provide important protection of arteries against an inflammatory stimulus and that IL-10 decreases iNOS-mediated impairment of vasorelaxation after LPS.

scholarly journals Deficient Humoral Responses Underlie Susceptibility to Toxoplasma gondii in CD4-Deficient Mice

2002 ◽  
Vol 70 (1) ◽  
pp. 185-191 ◽  
Author(s):  
Lawrence L. Johnson ◽  
Peter C. Sayles
Keyword(s):  
T Cells ◽  
Toxoplasma Gondii ◽  
Immune Serum ◽  
Wild Type ◽  
Ifn Γ ◽  
Resistance To Infection ◽  
Humoral Responses ◽  
Brain Cysts ◽  
Deficient Mice

ABSTRACT Resistance to infection with Toxoplasma gondii was studied in mice lacking CD4 expression. Such mice developed more brain cysts and survived for a shorter time than did wild-type controls after peroral infection with ME49 cysts. After immunization with the ts-4 strain of T. gondii, CD4-deficient mice exhibited impaired resistance to a challenge infection with virulent RH tachyzoites. Thus, deficient CD4 expression increases the susceptibility of mice to a primary peroral T. gondii infection with cysts and impairs their ability to be successfully vaccinated. CD8+ T cells from blood or spleens of Toxoplasma-infected, CD4-deficient mice expressed markers of activation at frequencies similar to those of infected wild-type mice. Production of IFN-γ in vitro was moderately depressed, and levels of Toxoplasma-specific immunoglobulin G2a in serum were substantially lower than in wild-type mice. Administration of Toxoplasma-immune serum to ts-4-vaccinated CD4-deficient mice significantly improved their resistance to RH challenge. Also, the survival of CD4-deficient mice chronically infected with ME49 was significantly prolonged by administration of immune serum. These results demonstrate that in addition to CD8+ T cells and IFN-γ, which are known to be critical for resistance, CD4+ cells also contribute significantly to protection against chronic T. gondii infections and against challenge infections with highly virulent tachyzoites in immunized mice via their role as helper cells for production of isotype-switched antibodies.

scholarly journals Endotoxin Priming Improves Clearance of Pseudomonas aeruginosa in Wild-Type and Interleukin-10 Knockout Mice

2005 ◽  
Vol 73 (11) ◽  
pp. 7340-7347 ◽  
Author(s):  
Tushar K. Varma ◽  
Megan Durham ◽  
Erle D. Murphey ◽  
Weihua Cui ◽  
Zhiyu Huang ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Knockout Mice ◽  
Systemic Infection ◽  
Interleukin 10 ◽  
Interleukin 12 ◽  
Systemic Clearance ◽  
Wild Type ◽  
Lps Challenge ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACT Endotoxin (lipopolysaccharide [LPS]) tolerance is an altered state of immunity caused by prior exposure to LPS, in which production of many cytokines, including gamma interferon (IFN-γ) and interleukin-12 (IL-12), are reduced but secretion of the anti-inflammatory cytokine IL-10 is increased in response to a subsequent LPS challenge. This pattern of cytokine production is also characteristic of postinflammatory immunosuppression. Therefore, we hypothesized that LPS-primed mice would exhibit an impaired ability to respond to systemic infection with the opportunistic pathogen Pseudomonas aeruginosa. We further hypothesized that depletion of IL-10 would reverse the endotoxin-tolerant state. To test this hypothesis, systemic clearance of Pseudomonas aeruginosa was measured for LPS-primed wild-type and IL-10-deficient mice. LPS-primed wild-type mice exhibited significant suppression of LPS-induced IFN-γ and IL-12 but increased IL-10 production in blood and spleen compared to levels exhibited by saline-primed wild-type mice. The suppressed production of IFN-γ and IL-12 caused by LPS priming was ablated in the spleens, but not blood, of IL-10 knockout mice. LPS-primed wild-type mice cleared Pseudomonas aeruginosa from lungs and blood more effectively than saline-primed mice. LPS-primed IL-10-deficient mice were particularly efficient in clearing Pseudomonas aeruginosa after systemic challenge. These studies show that induction of LPS tolerance enhanced systemic clearance of Pseudomonas aeruginosa and that this effect was augmented by neutralization of IL-10.

scholarly journals Stimulation of Interleukin-10 Production by Acidic β-Lactoglobulin-Derived Peptides Hydrolyzed with Lactobacillus paracasei NCC2461 Peptidases

2004 ◽  
Vol 11 (2) ◽  
pp. 266-271 ◽  
Author(s):  
Guénolée Prioult ◽  
Sophie Pecquet ◽  
Ismail Fliss
Keyword(s):  
Oral Tolerance ◽  
Immunosuppressive Agents ◽  
Interleukin 10 ◽  
Lactobacillus Paracasei ◽  
In Vitro Hydrolysis ◽  
Ifn Γ ◽  
Immunomodulatory Peptides ◽  
Β Lactoglobulin

ABSTRACT We have previously demonstrated that Lactobacillus paracasei NCC2461 may help to prevent cow's milk allergy in mice by inducing oral tolerance to β-lactoglobulin (BLG). To investigate the mechanisms involved in this beneficial effect, we examined the possibility that L. paracasei induces tolerance by hydrolyzing BLG-derived peptides and liberating peptides that stimulate interleukin-10 (IL-10) production. L. paracasei peptidases have been shown to hydrolyze tryptic-chymotryptic peptides from BLG, releasing numerous small peptides with immunomodulating properties. We have now shown that acidic tryptic-chymotryptic peptides stimulate splenocyte proliferation and gamma interferon (IFN-γ) production in vitro. Hydrolysis of these peptides with L. paracasei peptidases repressed the lymphocyte stimulation, up-regulated IL-10 production, and down-regulated IFN-γ and IL-4 secretion. L. paracasei NCC2461 may therefore induce oral tolerance to BLG in vivo by degrading acidic peptides and releasing immunomodulatory peptides stimulating regulatory T cells, which function as major immunosuppressive agents by secreting IL-10.

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