scholarly journals Gamma Interferon (IFN-γ) and IFN-γ-Inducing Cytokines Interleukin-12 (IL-12) and IL-18 Do Not Augment Infection-Stimulated Bone Resorption In Vivo

2004 ◽  
Vol 11 (1) ◽  
pp. 106-110 ◽  
Author(s):  
Hajime Sasaki ◽  
Khaled Balto ◽  
Nobuyuki Kawashima ◽  
Jean Eastcott ◽  
Katsuaki Hoshino ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Alveolar Bone ◽  
Interleukin 1 ◽  
Bone Destruction ◽  
Gamma Interferon ◽  
Interleukin 12 ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Ifn Γ

ABSTRACT Periapical granulomas are induced by bacterial infection of the dental pulp and result in destruction of the surrounding alveolar bone. In previous studies we have reported that the bone resorption in this model is primarily mediated by macrophage-expressed interleukin-1 (IL-1). The expression and activity of IL-1 is in turn modulated by a network of Th1 and Th2 regulatory cytokines. In the present study, the functional roles of the Th1 cytokine gamma interferon (IFN-γ) and IFN-γ-inducing cytokines IL-12 and IL-18 were determined in a murine model of periapical bone destruction. IL-12−/−, IL-18−/−, and IFN-γ−/− mice were subjected to surgical pulp exposure and infection with a mixture of four endodontic pathogens, and bone destruction was determined by microcomputed tomography on day 21. The results indicated that all IL-12−/−, IL-18−/−, and IFN-γ−/− mice had similar infection-stimulated bone resorption in vivo as wild-type control mice. Mice infused with recombinant IL-12 also had resorption similar to controls. IFN-γ−/− mice exhibited significant elevations in IL-6, IL-10, IL-12, and tumor necrosis factor alpha in lesions compared to wild-type mice, but these modulations had no net effect on IL-1α levels. Recombinant IL-12, IL-18, and IFN-γ individually failed to consistently modulate macrophage IL-1α production in vitro. We conclude that, at least individually, endogenous IL-12, IL-18, and IFN-γ do not have a significant effect on the pathogenesis of infection-stimulated bone resorption in vivo, suggesting possible functional redundancy in proinflammatory pathways.

scholarly journals Interleukin-6 Deficiency Increases Inflammatory Bone Destruction

2001 ◽  
Vol 69 (2) ◽  
pp. 744-750 ◽  
Author(s):  
Khaled Balto ◽  
Hajime Sasaki ◽  
Philip Stashenko
Keyword(s):  
Bone Resorption ◽  
Interleukin 1 ◽  
Bone Destruction ◽  
Fusobacterium Nucleatum ◽  
Wild Type ◽  
Periapical Lesions ◽  
Elevated Expression ◽  
Pulp Exposure ◽  
Anti Inflammatory

ABSTRACT Periapical bone destruction occurs as a consequence of pulpal infection. In previous studies, we showed that interleukin-1 (IL-1) is the primary stimulator of bone destruction in this model. IL-6 is a pleiotropic cytokine that is induced in these infections and has both pro- and anti-inflammatory activities. In the present study, we determined the role of IL-6 in regulating IL-1 expression and bone resorption. The first molars of IL-6 knockouts (IL-6−/−) and wild-type mice were subjected to surgical pulp exposure and infection with a mixture of four common pulpal pathogens, includingPrevotella intermedia, Fusobacterium nucleatum,Peptostreptococcus micros, and Streptococcus intermedius. Mice were killed after 21 days, and bone destruction and cytokine expression were determined. Surprisingly, bone destruction was significantly increased in IL-6−/− mice versus that in wild-type mice (by 30%; P < 0.001). In a second experiment, the effects of chronic (IL-6−/−) IL-6 deficiency and short-term IL-6 deficiency induced by in vivo antibody neutralization were determined. Both IL-6−/− (30%;P < 0.001) and anti-IL-6 antibody-treated mice (40%;P < 0.05) exhibited increased periapical bone resorption, compared to wild-type controls. The increased bone resorption in IL-6-deficient animals correlated with increases in osteoclast numbers, as well as with elevated expression of bone-resorptive cytokines IL-1α and IL-1β, in periapical lesions and with decreased expression of the anti-inflammatory cytokine IL-10. These data demonstrate that endogenous IL-6 expression has significant anti-inflammatory effects in modulating infection-stimulated bone destruction in vivo.

scholarly journals Gamma Interferon Positively Modulates Actinobacillus actinomycetemcomitans-Specific RANKL+ CD4+ Th-Cell-Mediated Alveolar Bone Destruction In Vivo

2005 ◽  
Vol 73 (6) ◽  
pp. 3453-3461 ◽  
Author(s):  
Yen-Tung A. Teng ◽  
Deeqa Mahamed ◽  
Bhagirath Singh
Keyword(s):  
Signaling Pathways ◽  
Alveolar Bone ◽  
Bone Destruction ◽  
Gamma Interferon ◽  
Actinobacillus Actinomycetemcomitans ◽  
Periodontal Tissues ◽  
Human T Cell ◽  
Th Cell ◽  
Ifn Γ

ABSTRACT Recent studies have shown the biological and clinical significance of signaling pathways of osteogenic cytokines RANKL-RANK/OPG in controlling osteoclastogenesis associated with bone pathologies, including rheumatoid arthritis, osteoporosis, and other osteolytic disorders. In contrast to the inhibitory effect of gamma interferon (IFN-γ) on RANKL-mediated osteoclastogenesis reported recently, alternative new evidence is demonstrated via studies of experimental periodontitis using humanized NOD/SCID and diabetic NOD mice and clinical human T-cell isolates from diseased periodontal tissues, where the presence of increasing IFN-γ is clearly associated with (i) enhanced Actinobacillus actinomycetemcomitans-specific RANKL-expressing CD4+ Th cell-mediated alveolar bone loss during the progression of periodontal disease and (ii) a concomitant and significantly increased coexpression of IFN-γ in RANKL(+) CD4+ Th cells. Therefore, there are more complex networks in regulating RANKL-RANK/OPG signaling pathways for osteoclastogenesis in vivo than have been suggested to date.

scholarly journals Resistance to Acute Babesiosis Is Associated with Interleukin-12- and Gamma Interferon-Mediated Responses and Requires Macrophages and Natural Killer Cells

2003 ◽  
Vol 71 (4) ◽  
pp. 2002-2008 ◽  
Author(s):  
Irma Aguilar-Delfin ◽  
Peter J. Wettstein ◽  
David H. Persing
Keyword(s):  
Nk Cells ◽  
Gamma Interferon ◽  
Interleukin 12 ◽  
No Production ◽  
Cytokine Responses ◽  
Early Production ◽  
Ifn Γ ◽  
Crucial Part

ABSTRACT We examined the role of the cytokines gamma interferon (IFN-γ) and interleukin-12 (IL-12) in the model of acute babesiosis with the WA1 Babesia. Mice genetically deficient in IFN-γ-mediated responses (IFNGR2KO mice) and IL-12-mediated responses (Stat4KO mice) were infected with the WA1 Babesia, and observations were made on the course of infection and cytokine responses. Levels of IFN-γ and IL-12 in serum increased 24 h after parasite inoculation. The augmented susceptibility observed in IFNGR2KO and Stat-4KO mice suggests that the early IL-12- and IFN-γ-mediated responses are involved in protection against acute babesiosis. Resistance appears to correlate with an increase in nitric oxide (NO) production. In order to assess the contribution of different cell subsets to resistance against the parasite, we also studied mice lacking B cells, CD4+ T cells, NK cells, and macrophages. Mice genetically deficient in B lymphocytes or CD4+ T lymphocytes were able to mount protective responses comparable to those of immunosufficient mice. In contrast, in vivo depletion of macrophages or NK cells resulted in elevated susceptibility to the infection. Our observations suggest that a crucial part of the response that protects from the pathogenic Babesia WA1 is mediated by macrophages and NK cells, probably through early production of IL-12 and IFN-γ, and induction of macrophage-derived effector molecules like NO.

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 Autoinducer-2 and QseC Control Biofilm Formation and In Vivo Virulence of Aggregatibacter actinomycetemcomitans

2010 ◽  
Vol 78 (7) ◽  
pp. 2919-2926 ◽  
Author(s):  
Elizabeth A. Novak ◽  
HanJuan Shao ◽  
Carlo Amorin Daep ◽  
Donald R. Demuth
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Biofilm Formation ◽  
Alveolar Bone ◽  
Wild Type ◽  
Two Component System ◽  
Component System ◽  
Autoinducer 2 ◽  
Two Component

ABSTRACT Biofilm formation by the periodontal pathogen Aggregatibacter actinomycetemcomitans is dependent upon autoinducer-2 (AI-2)-mediated quorum sensing. However, the components that link the detection of the AI-2 signal to downstream gene expression have not been determined. One potential regulator is the QseBC two-component system, which is part of the AI-2-dependent response pathway that controls biofilm formation in Escherichia coli. Here we show that the expression of QseBC in A. actinomycetemcomitans is induced by AI-2 and that induction requires the AI-2 receptors, LsrB and/or RbsB. Additionally, inactivation of qseC resulted in reduced biofilm growth. Since the ability to grow in biofilms is essential for A. actinomycetemcomitans virulence, strains that were deficient in QseC or the AI-2 receptors were examined in an in vivo mouse model of periodontitis. The ΔqseC mutant induced significantly less alveolar bone resorption than the wild-type strain (P < 0.02). Bone loss in animals infected with the ΔqseC strain was similar to that in sham-infected animals. The ΔlsrB, ΔrbsB, and ΔlsrB ΔrbsB strains also induced significantly less alveolar bone resorption than the wild type (P < 0.03, P < 0.02, and P < 0.01, respectively). However, bone loss induced by a ΔluxS strain was indistinguishable from that induced by the wild type, suggesting that AI-2 produced by indigenous microflora in the murine oral cavity may complement the ΔluxS mutation. Together, these results suggest that the QseBC two-component system is part of the AI-2 regulon and may link the detection of AI-2 to the regulation of downstream cellular processes that are involved in biofilm formation and virulence of A. actinomycetemcomitans.

scholarly journals Respiratory Tract Infection with Mycoplasma pneumoniae in Interleukin-12 Knockout Mice Results in Improved Bacterial Clearance and Reduced Pulmonary Inflammation

2006 ◽  
Vol 75 (1) ◽  
pp. 236-242 ◽  
Author(s):  
C. M. Salvatore ◽  
M. Fonseca-Aten ◽  
K. Katz-Gaynor ◽  
A. M. Gomez ◽  
A. Mejias ◽  
...  
Keyword(s):  
Respiratory Disease ◽  
Mycoplasma Pneumoniae ◽  
Pulmonary Inflammation ◽  
Airway Hyperreactivity ◽  
Interleukin 12 ◽  
Enzyme Linked Immunosorbent Assay ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACT Mycoplasma pneumoniae is a leading cause of pneumonia and is associated with asthma. Evidence links M. pneumoniae respiratory disease severity with interleukin-12 (IL-12) concentration in respiratory secretions. We evaluated the microbiologic, inflammatory, and pulmonary function indices of M. pneumoniae pneumonia in IL-12 (p35) knockout (KO) mice and wild-type (WT) mice to determine the role of IL-12 in M. pneumoniae respiratory disease. Eight-week-old wild-type BALB/c mice and 8-week-old IL-12 (p35) KO BALB/c mice were inoculated once intranasally with 107 CFU of M. pneumoniae. Mice were evaluated at days 2, 4, and 7 after inoculation. Outcome variables included quantitative bronchoalveolar lavage (BAL) M. pneumoniae culture, lung histopathologic scores (HPS), BAL cytokine concentrations determined by enzyme-linked immunosorbent assay (tumor necrosis factor alpha [TNF-α], gamma interferon [IFN-γ], IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, and granulocyte-macrophage colony-stimulating factor) and plethysmography, before and after methacholine, to assess airway obstruction (AO) and airway hyperreactivity (AHR). IL-12 (p35) KO mice infected with M. pneumoniae were found to have significantly lower BAL M. pneumoniae concentrations compared with M. pneumoniae-infected WT mice. Lung HPS and the parenchymal pneumonia subscores (neutrophilic alveolar infiltrate), as well as AO, were significantly lower in infected KO mice. No difference was found for AHR. Infected KO mice had significantly lower BAL concentrations of IFN-γ than WT mice; a trend toward lower BAL concentrations was observed for IL-10 (P = 0.065) and TNF-α (P = 0.078). No differences were found for IL-1β, IL-2, IL-4, IL-5, or IL-6. The lack of IL-12 in experimental M. pneumoniae pneumonia was associated with less severe pulmonary disease and more rapid microbiologic and histologic resolution.

scholarly journals In Vivo Regulation of Replicative Legionella pneumophila Lung Infection by Endogenous Interleukin-12

1998 ◽  
Vol 66 (1) ◽  
pp. 65-69 ◽  
Author(s):  
J. K. Brieland ◽  
D. G. Remick ◽  
M. L. LeGendre ◽  
N. C. Engleberg ◽  
J. C. Fantone
Keyword(s):  
Legionella Pneumophila ◽  
Lung Infection ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Protein Levels ◽  
Tnf Α ◽  
Factor Alpha ◽  
Ifn Γ

ABSTRACT The in vivo role of endogenous interleukin 12 (IL-12) in modulating intrapulmonary growth of Legionella pneumophila was assessed by using a murine model of replicative L. pneumophila lung infection. Intratracheal inoculation of A/J mice with virulent bacteria (106 L. pneumophilacells per mouse) resulted in induction of IL-12, which preceded clearance of the bacteria from the lung. Inhibition of endogenous IL-12 activity, via administration of IL-12 neutralizing antiserum, resulted in enhanced intrapulmonary growth of the bacteria within 5 days postinfection (compared to untreated L. pneumophila-infected mice). Because IL-12 has previously been shown to modulate the expression of cytokines, including gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and IL-10, which regulate L. pneumophila growth, immunomodulatory effects of endogenous IL-12 on intrapulmonary levels of these cytokines during replicative L. pneumophila lung infection were subsequently assessed. Results of these experiments demonstrated that TNF-α activity was significantly lower, while protein levels of IFN-γ and IL-10 in the lung were similar, in L. pneumophila-infected mice administered IL-12 antiserum, compared to similarly infected untreated mice. Together, these results demonstrate that IL-12 is critical for resolution of replicativeL. pneumophila lung infection and suggest that regulation of intrapulmonary growth of L. pneumophila by endogenous IL-12 is mediated, at least in part, by TNF-α.

scholarly journals Obligatory Role of Gamma Interferon for Host Survival in a Murine Model of Infection with Burkholderia pseudomallei

1999 ◽  
Vol 67 (7) ◽  
pp. 3593-3600 ◽  
Author(s):  
P. Santanirand ◽  
V. S. Harley ◽  
D. A. B. Dance ◽  
B. S. Drasar ◽  
G. J. Bancroft
Keyword(s):  
Murine Model ◽  
Chronic Infection ◽  
Burkholderia Pseudomallei ◽  
Lethal Dose ◽  
Gamma Interferon ◽  
Interleukin 12 ◽  
Protective Mechanism ◽  
Human Pathology ◽  
Ifn Γ

ABSTRACT Burkholderia pseudomallei, the causative agent of melioidosis, is a gram-negative bacterium capable of causing either acute lethal sepsis or chronic but eventually fatal disease in infected individuals. However, despite the clinical importance of this infection in areas where it is endemic, there is essentially no information on the mechanisms of protective immunity to the bacterium. We describe here a murine model of either acute or chronic infection with B. pseudomallei in Taylor Outbred (TO) mice which mimics many features of the human pathology. Intraperitoneal infection of TO mice at doses of >106 CFU resulted in acute septic shock and death within 2 days. In contrast, at lower doses mice were able to clear the inoculum from the liver and spleen over a 3- to 4-week period, but persistence of the organism at other sites resulted in a chronic infection of between 2 and 16 months duration which was eventually lethal in all of the animals tested. Resistance to acute infection with B. pseudomallei was absolutely dependent upon the production of gamma interferon (IFN-γ) in vivo. Administration of neutralizing monoclonal antibody against IFN-γ lowered the 50% lethal dose from >5 × 105 to ca. 2 CFU and was associated with 8,500- and 4,400-fold increases in the bacterial burdens in the liver and spleen, respectively, together with extensive destruction of lymphoid architecture in the latter organ within 48 h. Neutralization of either tumor necrosis factor alpha or interleukin-12 but not granulocyte-macrophage colony-stimulating factor, also increased susceptibility to infection in vivo. Together, these results provide the first evidence of a host protective mechanism against B. pseudomallei. The rapid production of IFN-γ within the first day of infection determines whether the infection proceeds to an acute lethal outcome or becomes chronic.

scholarly journals Bone Resorption Caused by Three Periodontal Pathogens In Vivo in Mice Is Mediated in Part by Prostaglandin

1998 ◽  
Vol 66 (9) ◽  
pp. 4158-4162 ◽  
Author(s):  
Yuval Zubery ◽  
Colin R. Dunstan ◽  
Beryl M. Story ◽  
Lakshmyya Kesavalu ◽  
Jeffrey L. Ebersole ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Alveolar Bone ◽  
Tissue Injury ◽  
Bone Destruction ◽  
Fusobacterium Nucleatum ◽  
Host Responses ◽  
Periodontal Pathogens ◽  
Tissue Destruction

ABSTRACT Gingival inflammation, bacterial infection, alveolar bone destruction, and subsequent tooth loss are characteristic features of periodontal disease, but the precise mechanisms of bone loss are poorly understood. Most animal models of the disease require injury to gingival tissues or teeth, and the effects of microorganisms are thus complicated by host responses to tissue destruction. To determine whether three putative periodontal pathogens, Porphyromonas gingivalis, Campylobacter rectus, andFusobacterium nucleatum, could cause localized bone resorption in vivo in the absence of tissue injury, we injected live or heat-killed preparations of these microorganisms into the subcutaneous tissues overlying the calvaria of normal mice once daily for 6 days and then examined the bones histologically. We found that all three microorganisms (both live and heat killed) stimulated bone resorption and that the strain of F. nucleatum used appeared to be the strongest inducer of osteoclast activity. Treatment of the mice concomitantly with indomethacin reduced but did not completely inhibit bone resorption by these microorganisms, suggesting that their effects were mediated, in part, by arachidonic acid metabolites (e.g., prostaglandins). Our findings indicate that these potential pathogens can stimulate bone resorption locally when placed beside a bone surface in vivo in the absence of prior tissue injury and support a role for them in the pathogenesis of bone loss around teeth in periodontitis.

scholarly journals Immune Response to Nocardia brasiliensisAntigens in an Experimental Model of Actinomycetoma in BALB/c Mice

1999 ◽  
Vol 67 (5) ◽  
pp. 2428-2432 ◽  
Author(s):  
Mario C. Salinas-Carmona ◽  
Ernesto Torres-Lopez ◽  
Alma I. Ramos ◽  
Angel Licon-Trillo ◽  
Daniel Gonzalez-Spencer
Keyword(s):  
Stimulation Index ◽  
Interleukin 1 ◽  
Bone Destruction ◽  
Complete Healing ◽  
Immunoglobulin M ◽  
Fistula Formation ◽  
Enzyme Linked Immunosorbent Assay ◽  
Polymorphonuclear Cells ◽  
Necrosis Factor Alpha ◽  
Ifn Γ

ABSTRACT Nine- to twelve-week-old BALB/c mice were injected in footpads with 107 CFU of a Nocardia brasiliensis cell suspension. Typical actinomycetoma lesions, characterized by severe local inflammation with abscess and fistula formation, were fully established by day 28 after infection. These changes presented for 90 days, and then tissue repair with scar formation slowly appeared, with complete healing after 150 days of infection. Some animals developed bone destruction in the affected area. Histopathology showed an intense inflammatory response, with polymorphonuclear cells and hyaloid material around the colonies of the bacteria, some of which were discharged from draining abscesses. Sera from experimental animals were analyzed by Western blotting, and immunodominant antigens P61 and P24 were found as major targets for antibody response. Anti-P24 immunoglobulin M (IgM) isotype antibodies were present as early as 7 days, IgG peaking 45 days after infection. Lymphocyte proliferation with spleen and popliteal lymph node cells demonstrated thymidine incorporation at 7 days after infection, the stimulation index decreasing by day 60. Levels of interleukin-1 (IL-1), IL-2, IL-4, IL-6, tumor necrosis factor alpha, and gamma interferon (IFN-γ) were determined by enzyme-linked immunosorbent assay in the sera of infected animals. The circulating levels of IFN-γ increased more than 10 times the basal levels; levels of IL-4, IL-6 and IL-10 also increased during the first 4 days of infection.

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