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1.
Inflammation ; 36(6): 1295-303, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23807051

ABSTRACT

Murine gammaherpesvirus 68 (MHV68) is a natural rodent pathogen that has been used as a model to study the pathogenesis of human gammaherpesviruses. Like other herpesviruses, MHV68 causes acute infection and establishes life-long latency in the host. Recently, it has been shown that mice latently infected with MHV68 have resistance to unrelated pathogens in secondary infection models. We therefore hypothesized that latent MHV68 infection could modulate the host response to influenza A virus. To test this hypothesis, mice were infected intranasally with influenza virus following the establishment of MHV68 latency. Mice latently infected with MHV68 showed significantly higher survival to influenza A virus infection than did PBS mock-infected mice. Latent MHV68 infection led to lower influenza viral loads and decreased inflammatory pathology in the lungs. Alveolar macrophages of mice latently infected with MHV68 showed activated status, and adoptive transfer of those activated macrophages into mice followed the infection with influenza A virus had significantly greater survival rates than control mice, suggesting that activated alveolar macrophages are a key mechanistic component in protection from secondary infections.


Subject(s)
Influenza A virus/immunology , Macrophages, Alveolar/immunology , Orthomyxoviridae Infections/immunology , Rhadinovirus/immunology , Virus Latency/immunology , Adaptive Immunity , Adoptive Transfer , Animals , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Female , Inflammation/virology , Macrophage Activation/immunology , Mice , Mice, Inbred BALB C , Orthomyxoviridae Infections/prevention & control , Survival , Viral Load
2.
Front Immunol ; 4: 10, 2013.
Article in English | MEDLINE | ID: mdl-23386849

ABSTRACT

Granulomas represent a spectrum of inflammatory sequestration responses that may be initiated by a variety of agents, including non-infectious environmental factors and infectious microbial pathogens. Although this reaction is designed to be protective, the associated tissue injury is often responsible for a profound degree of pathology. While many of the mechanisms that sustain the development of the granuloma are enigmatic, it is accepted that the maintenance of this inflammatory process is dependent upon dynamic interactions between an inciting agent, inflammatory mediators, various immune and inflammatory cells, and structural cells of the involved tissue. The best studied of the host-dependent processes during granuloma development is the innate and adaptive immune response. The innate immune response by antigen-presenting cells [APCs; dendritic cells (DCs) and macrophages] is initiated quickly to protect from overwhelming pathogens, but with time, can also activate the adaptive immune response. APCs, essential regulators of the innate immune response, can respond to microbial ligands through Toll-like receptors (TLRs), which function in the recognition of microbial components and play an important role to link the innate and adaptive immune responses. CD4(+) T helper (Th) cells are essential regulators of adaptive immune responses and inflammatory diseases. Recently, the Notch system has been shown to be an important bridge between APCs and T cell communication circuits. In the present review, we discuss recent findings that explore the mechanisms in the linkage of innate and adaptive immunity, including granulomatous formation though TLRs and Notch activation.

3.
J Leukoc Biol ; 92(1): 59-65, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22459946

ABSTRACT

The lung is one of the most immunologically challenged organs and can be affected by a number of pathogens, including bacteria, virus, fungi, and parasites. The development and chronicity of pulmonary infection are determined by the early innate response to the pathogenic stimuli and are regulated at multiple levels. Initial studies have indicated that the interaction of Notch and Notch ligands plays a critical role during development, and further, the Notch system is an important bridge between APCs and T cell communication circuits. APCs are essential regulators of the innate immune response. They can respond to PAMPs through PRRs, which function in the recognition of pathogenic components and play an important role in the innate and adaptive immune response. T cells are essential regulators of adaptive immune responses and infectious diseases. However, the role of the Notch system in the cross-talk between APC and T cells during pulmonary infection is still poorly understood. In the present review, we discuss recent findings that explore the mechanisms underlying the role of Notch signaling in the linkage of innate and adaptive immunity, including pulmonary infection though PPRs and Notch activation.


Subject(s)
Adaptive Immunity , Immunity, Innate , Receptors, Notch/metabolism , Respiratory Tract Infections/immunology , Respiratory Tract Infections/metabolism , Animals , Humans
4.
Exp Cell Res ; 317(5): 613-9, 2011 Mar 10.
Article in English | MEDLINE | ID: mdl-21376174

ABSTRACT

Chemokines are key mediators of leukocyte recruitment during pathogenic insult and also play a prominent role in homeostasis. While most chemokine receptors bind to multiple chemokines, CCR6 is unique in that this receptor is one of only a few that can bind only a single chemokine ligand, CCL20. CCR6 is an important receptor that is involved in regulating several aspects of mucosal immunity, including the ability to mediate the recruitment of immature dendritic cells (DCs) and mature DCs, and professional antigen presenting cells (APCs) to the sites of epithelial inflammation. Further, CCR6 mediates the homing of both CD4(+) T (T-helper; Th) cells and DCs to the gut mucosal lymphoid tissue. DCs, which are known to be essential immune cells in innate immunity and in the initiation of adaptive immunity, play a central role in initiating a primary immune response. Herein, we summarize the role of CCR6 in immune responses at epithelial and mucosal sites in both the lung and gut based on a review of the current literature.


Subject(s)
Intestinal Mucosa/immunology , Lung/immunology , Receptors, CCR6/immunology , Animals , Chemokines/immunology , Humans , Immunity , Intestinal Mucosa/cytology , Lung/cytology
5.
Crit Care Med ; 37(5): 1567-73, 2009 May.
Article in English | MEDLINE | ID: mdl-19325479

ABSTRACT

OBJECTIVE: This study examined the effectiveness of prospective stratification to identify and target high-dose glucocorticoid therapy for subjects developing lethal sepsis. DESIGN: Prospective, randomized, laboratory-controlled experiment. SETTING: University research laboratory. SUBJECTS: Adult female outbred CD-1 mice. INTERVENTIONS: Mice (n = 88) were subjected to sepsis induced by cecal ligation and puncture (CLP). Mice were prospectively divided into two groups, predicted to die (P-DIE) or predicted to live (P-LIVE), based on plasma levels of interleukin (IL)-6 obtained 6 hours after CLP. Following stratification, dexamethasone (DEX, 2.5 mg/kg, two doses) was administered to half the animals in each group whereas the other half received saline. MEASUREMENTS AND MAIN RESULTS: Without stratification, DEX conferred no benefit. In the P-DIE group, none of saline-treated mice lived whereas 40% of the DEX-treated mice survived. Of the nonsurvivors, 67% had death delayed by 24-48 hours compared with saline-treated mice. Twenty-four hours post-CLP, the lymphocyte count was higher in the P-DIE than in the P-LIVE mice regardless of treatment status, whereas the opposite trend was noted for neutrophils. Plasma cytokine and cytokine inhibitor levels in the saline-treated animals showed that levels in the P-DIE group were higher than those in the P-LIVE group (e.g., 60 vs. 10 ng/mL for IL-6 and 453 vs.129 ng/mL for IL-1 receptor antagonist). Interestingly, DEX therapy did not decrease 24 hours post-CLP circulating cytokines in either the P-DIE or the P-LIVE group. CONCLUSIONS: Following CLP-induced sepsis, early and accurate survival prediction allows targeted immunosuppression that improves survival. Better survival occurred without suppression of the typical proinflammatory mediators, suggesting that the deaths were not mediated by excessive cytokine-driven inflammation. Nonspecific anti-inflammatory/immunosuppressive treatment administered to more rigorously defined cohorts may be more successful than mediator-specific drugs used indiscriminately.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Dexamethasone/pharmacology , Inflammation Mediators/blood , Interleukin-6/blood , Sepsis/blood , Sepsis/drug therapy , Animals , Area Under Curve , Biomarkers/blood , Confidence Intervals , Cytokines/blood , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Administration Schedule , Enzyme-Linked Immunosorbent Assay , Female , Interleukin-1/blood , Mice , Mice, Inbred Strains , Predictive Value of Tests , Probability , Random Allocation , Sepsis/immunology , Survival Rate
6.
J Interferon Cytokine Res ; 25(10): 587-94, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16241857

ABSTRACT

Interferon-gamma (IFN-gamma) is a pleiotropic cytokine with potent antitumor effects, both in vitro and in vivo. The antitumor activity of IFN-gamma is mediated in part through IFN regulatory factor-1 (IRF-1) and may be blocked by IRF-2. To test our hypothesis that some tumors escape the antitumor effects of IFN-gamma by cellular changes reflected in IRF-1 and IRF-2 expression, we examined IRF-1 and IRF-2 expression in tissue microarrays (TMA) containing 187 specimens of clinically defined invasive breast carcinoma. TMAs (Cooperative Breast Cancer Tissue Resource [CBCTR], National Cancer Institute [NCI]) were stained and then scored by three evaluators blinded to the patients' clinical status. After final scoring, the CBCTR provided the available clinical data for each patient. Whether sorted by carcinoma type or for all data together, statistical analysis showed a significant positive correlation between IRF-1 and IRF-2 expression (p = 0.01) and a negative correlation between IRF-1 expression and tumor grade (p = 0.005). IRF-1 expression is consistent with its role as a tumor suppressor; high-grade breast carcinomas were less likely to maintain expression of IRF-1, a finding consistent with a role for IRF-1 as a tumor suppressor. Further, tumors maintained expression of IRF-2 if there was coincident expression of IRF-1. These data support a model in which alterations of the expression of intracellular effectors of IFN-gamma signaling may diminish the immune-mediated tumor control mechanisms of IFN-gamma.


Subject(s)
Breast Neoplasms/metabolism , Carcinoma/metabolism , Gene Expression Regulation, Neoplastic , Interferon Regulatory Factor-1/biosynthesis , Interferon Regulatory Factor-2/biosynthesis , Tissue Array Analysis , Breast Neoplasms/immunology , Breast Neoplasms/pathology , Carcinoma/immunology , Carcinoma/pathology , Female , Gene Expression Regulation, Neoplastic/immunology , Humans , Interferon Regulatory Factor-1/immunology , Interferon Regulatory Factor-2/immunology , Interferon-gamma/immunology , Signal Transduction/immunology , Tissue Array Analysis/methods , Tumor Escape/immunology
7.
J Interferon Cytokine Res ; 23(11): 621-30, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14651776

ABSTRACT

The aim of the present work was to evaluate the induction and localization of Stat1, interferon (IFN) regulatory factor-1 (IRF-1), and IRF-2 after IFN-gamma exposure of human breast cancer cell lines, SKBR3, MDA468, MCF7, and BT20. Results from growth assays, Western staining, electrophoretic mobility shift assay (EMSA), and immunohistochemical staining were collated to test our hypothesis that immunohistochemical analysis of Stat1, IRF-1, and IRF-2 would provide additional information about the functionality of the IFN-gamma signaling pathway in human tumor lines. EMSA results showed that in each of four cell lines, Stat1 expression was increased and demonstrated functional activity after IFN-gamma stimulation. Western and EMSA analysis showed upregulation of IRF-1 but not IRF-2 in each cell line. Confocal microscopy of cells stained for Stat1, IRF-1, and IRF-2 confirmed the results and also provided novel information about the intracellular localization of proteins and intercellular variations in responses. The proportion of cells with IRF-1 stimulation and translocation was positively correlated with the IFN-gamma growth suppression in vitro. In conclusion, using four independent assays, we have demonstrated that heterogeneity in IFN-gamma-mediated upregulation of signal transduction proteins can be detected in vitro and that these differences can explain distinct cellular growth effects.


Subject(s)
Breast Neoplasms/metabolism , Cell Division/drug effects , DNA-Binding Proteins/metabolism , Interferon-gamma/pharmacology , Phosphoproteins/metabolism , Repressor Proteins , Trans-Activators/metabolism , Transcription Factors , Antibodies, Monoclonal , Blotting, Western , Breast Neoplasms/pathology , Cell Line, Tumor , Female , Gene Expression Regulation , Humans , Interferon Regulatory Factor-1 , Interferon Regulatory Factor-2 , Microscopy, Confocal , Recombinant Proteins , STAT1 Transcription Factor , Signal Transduction
8.
J Interferon Cytokine Res ; 23(9): 501-11, 2003 Sep.
Article in English | MEDLINE | ID: mdl-14565859

ABSTRACT

Interferon (IFN) regulatory factor-1 (IRF-1) and IRF-2 play opposing roles in the regulation of many IFN-gamma-inducible genes. To investigate the signal transduction pathway in response to IFN-gamma in light of differences in growth effects, we selected four human breast carcinoma cell lines based on a spectrum of growth inhibition by IFN-gamma. MDA468 growth was markedly inhibited by IFN-gamma, and it showed substantial induction of IRF-1 mRNA but little IRF-2 induction. SKBR3 showed little growth inhibition and little induction of IRF-1 mRNA but significant induction of IRF-2 mRNA. HS578T and MDA436 growth inhibition and IRF-1/IRF-2 induction were intermediate. All four cell lines showed intact receptor at the cell surface and Stat1 translocation to the nucleus by immunostaining. By EMSA, there were marked differences in the induced ratio of IRF-1 and IRF-2 binding activity between the cell lines that correlated with growth inhibition. Finally, antisense oligonucleotides specific for IRF-1 attenuated IFN-gamma growth inhibition in MDA436 and MDA468, confirming the direct role of IRF-1 in IFN-gamma growth inhibition. Induction of IRF-1 causes growth inhibition in human breast cancer cell lines, and induction of IRF-2 can oppose this. The relative induction of IRF-1 to IRF-2 is a critical control point in IFN-gamma response.


Subject(s)
Breast Neoplasms/metabolism , Carcinoma/metabolism , DNA-Binding Proteins/metabolism , Interferon-gamma/metabolism , Phosphoproteins/metabolism , Repressor Proteins , Transcription Factors , DNA-Binding Proteins/genetics , Female , Humans , Interferon Regulatory Factor-1 , Interferon Regulatory Factor-2 , Interferon-gamma/antagonists & inhibitors , Oligonucleotides, Antisense/pharmacology , Phosphoproteins/genetics , Protein Transport , RNA, Messenger/metabolism , Receptors, Interferon/metabolism , Reverse Transcriptase Polymerase Chain Reaction , STAT1 Transcription Factor , Trans-Activators/metabolism , Tumor Cells, Cultured , Interferon gamma Receptor
9.
Cancer Res ; 62(2): 445-9, 2002 Jan 15.
Article in English | MEDLINE | ID: mdl-11809694

ABSTRACT

Laparoscopic colectomy for curable colon cancer may result in the development of abdominal wall implants because of disseminated disease and the favorable environment of the wound site for cell implantation. Injection of disaggregated human GW39 colon cancer cells into the hamster peritoneum represents a model of tumor spillage that may occur during dissection, manipulation, resection, and extraction of tumor during surgery in the clinical setting. Using this well-established animal model, we tested the efficacy of (64)Cu-pyruvaldehyde-bis(N(4)-methylthiosemicarbazone) ((64)Cu-PTSM) in inhibiting tumor cell implantation in trocar wound sites. Anesthetized hamsters had four 5-mm trocars inserted through the anterior abdominal wall. GW39 cells ( approximately 3.2 x 10(4) cells in 0.5 ml) were injected into the peritoneum through a midline incision. Ten min later, hamsters were randomized to receive 5, 3, or 1 mCi of (64)Cu-PTSM through the same midline incision. High-resolution magnetic resonance imaging and microPET were used to monitor tumor volume and morphology after surgery. After 7 weeks, animals were sacrificed, and trocar and midline wounds were harvested for macroscopic and histological analysis. No macroscopic tumor was found in any of the group treated with 5 mCi of (64)Cu-PTSM, whereas 96% of the wound sites in the group treated with saline had macroscopic tumor growth (P < 0.001). This study demonstrates the therapeutic potential of (64)Cu-PTSM in inhibiting cancer cell implantation and growth at doses well below the maximum tolerated dose, with no signs of toxicity to the hamsters.


Subject(s)
Abdominal Neoplasms/prevention & control , Abdominal Neoplasms/secondary , Laparoscopy/adverse effects , Neoplasm Seeding , Organometallic Compounds/pharmacology , Thiosemicarbazones/pharmacology , Abdominal Muscles/pathology , Abdominal Neoplasms/diagnostic imaging , Abdominal Neoplasms/metabolism , Animals , Cell Division/drug effects , Colonic Neoplasms/diagnostic imaging , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Colonic Neoplasms/therapy , Copper Radioisotopes , Cricetinae , Magnetic Resonance Imaging , Mesocricetus , Organometallic Compounds/pharmacokinetics , Radiopharmaceuticals/pharmacokinetics , Radiopharmaceuticals/pharmacology , Thiosemicarbazones/pharmacokinetics , Tissue Distribution , Tomography, Emission-Computed , Xenograft Model Antitumor Assays
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