Biomedical subjects

Gwo-Hsiao Chen

Publications and source records attributed to Gwo-Hsiao Chen.

7 recordsLinked to original sources

PubMed2006

Differential regulation by leukotrienes and calcium of Fc gamma receptor-induced phagocytosis and Syk activation in dendritic cells versus macrophages.

Macrophage (MØ) phagocytosis via the Fc receptor for immunoglobulin G (Fc gammaR) requires the spleen tyrosine kinase (Syk) and serves an important antimicrobial function. We have reported previously that Fc gammaR-mediated ingestion and Syk activation in MØ are amplified by and depend on the proinflammatory lipid mediator leukotriene B4 (LTB4). Although Fc gammaR-mediated ingestion is also important for antigen uptake, there is no information about LTB4 regulation of these processes in dendritic cells (DCs). In this study, we compared murine bone marrow (BM)-derived DCs to MØ from BM, peritoneum, and the pulmonary alveolar space. Neither phagocytosis nor Syk activation in DCs was influenced by exogenous LTB4. Unlike the various MØ populations, Syk activation in DCs was likewise unaffected by pharmacologic or genetic strategies to inhibit endogenous LTB4 synthesis or to block the high-affinity LTB4 receptor BLT1. DCs were refractory to regulation by LTB4 despite the fact that they expressed BLT1 and mobilized intracellular calcium in response to its ligation. This resistance to LTB4 in DCs instead reflected the fact that in contrast to MØ, Syk activation in DCs was itself entirely independent of calcium. These results identify a fundamental difference in Fc gammaR signaling between DCs and MØ, which may relate to the divergent, functional consequences of target ingestion in the two cell types.

Animals↗

PubMed2006

Short communication: differences between macrophages and dendritic cells in the cyclic AMP-dependent regulation of lipopolysaccharide-induced cytokine and chemokine synthesis.

Cyclic adenosine monophosphate (cAMP) is an intracellular signaling molecule responsible for directing cellular responses to extracellular signals. Once believed to signal exclusively through its ability to bind protein kinase A (PKA), recent research has revealed alternative cAMP-binding targets involved in PKA-independent processes. In this study we addressed the hypothesis that the guanine nucleotide exchange protein directly activated by cAMP (Epac-1) and PKA differentially regulate inflammatory mediator production in distinct phagocytic cell types. To accomplish this, we compared the release of cAMP-regulated polypeptide inflammatory mediators in both macrophages (obtained from the lung and peritoneum) and bone marrow-derived dendritic cells (DCs) stimulated with bacterial endotoxin. Using the highly selective Epac-1 and PKA activating cAMP analogs 8-pCPT-2 -O-Me-cAMP and 6-Bnz-cAMP, respectively, we found that macrophages differ from DCs in the involvement of these distinct cAMP pathways in modulating inflammatory mediator release in response to endotoxin. Whereas the regulation of cytokine and chemokine production in macrophages by cAMP was solely dependent on PKA, we found that both Epac-1 and PKA activation could regulate mediator production in DCs. This finding may be important in the pharmacologic regulation of immune responses through manipulation of cAMP signaling cascades and contributes to our understanding of the differences between these cell types.

Animals↗

PubMed2005

Transient neutralization of tumor necrosis factor alpha can produce a chronic fungal infection in an immunocompetent host: potential role of immature dendritic cells.

The mechanisms underlying induction of immune dysregulation and chronic fungal infection by a transient tumor necrosis factor alpha (TNF-alpha) deficiency remain to be defined. The objective of our studies was to determine the potential contribution of neutropenia and immature dendritic cells to the immune deviation. Administration of an anti-TNF-alpha monoclonal antibody at day 0 neutralized TNF-alpha only during the first week of a pulmonary Cryptococcus neoformans infection. Transient neutralization of TNF-alpha resulted in transient depression of interleukin-12 (IL-12), monocyte chemotactic protein 1 (MCP-1), and gamma interferon (IFN-gamma) production but permanently impaired long-term clearance of the infection from the lungs even after the levels of these cytokines increased and a vigorous inflammatory response developed. Early neutrophil recruitment was defective in the absence of TNF-alpha. However, as demonstrated by neutrophil depletion studies, this did not account for the decrease in IL-12 and IFN-gamma levels and did not play a role in establishing chronic pulmonary cryptococcal infection. Transient TNF-alpha neutralization also produced a deficiency in CD11c(+) MHC II(+) cells and IL-12 in the lymph nodes, potentially implicating a defect in mature dendritic cell trafficking. Transfer of cryptococcal antigen-pulsed immature dendritic cells into naive mice prior to intratracheal challenge resulted in the development of a nonprotective immune response to C. neoformans that was similar to that observed in anti-TNF-alpha-treated mice (increased IL-4, IL-5, and IL-10 levels, pulmonary eosinophilia, and decreased clearance). Thus, stimulation of an antifungal response by immature dendritic cells can result in an immune deviation similar to that produced by transient TNF-alpha deficiency, identifying a new mechanism by which a chronic fungal infection can occur in an immunocompetent host.

Animals↗

PubMed2005

The gamma interferon receptor is required for the protective pulmonary inflammatory response to Cryptococcus neoformans.

Mice with a null deletion mutation in the gamma interferon (IFN-gamma) receptor gene were used to study the role of IFN-gamma responsiveness during experimental pulmonary cryptococcosis. Cryptococcus neoformans was inoculated intratracheally into mice lacking the IFN-gamma receptor gene (IFN-gammaR-/-) and into control mice (IFN-gammaR+/+). The numbers of CFU in lung, spleen, and brain were determined to assess clearance; cytokines produced by lung leukocytes were measured, and survival curves were generated. In the present study, we demonstrate the following points. (i) IFN-gammaR-/- mice are markedly more susceptible to C. neoformans infection than IFN-gammaR+/+ mice. (ii) In the absence of IFN-gamma signaling, pulmonary CFU continue to increase over the course of infection, and the infection disseminates to the brain. (iii) In the absence of IFN-gamma receptor, recruitment of inflammatory cells in response to pulmonary cryptococcal infection is not impaired. (iv) At week 5 postinfection, IFN-gammaR-/- mice have recruited greater numbers of leukocytes into their lungs, with neutrophils, eosinophils, and lymphocytes accounting for this cellular increase. (v) IFN-gamma signaling is required for the development of a T1 over a T2 immune response in the lung following cryptococcal infection. These results indicate that in the absence of IFN- gamma responsiveness, even though the recruitment of pulmonary inflammatory cells is not impaired and the secretion of IFN-gamma is not affected, IFN-gammaR-/- mice do not have the ability to resolve the cryptococcal infection. In conclusion, our data suggest that proper functional IFN-gamma signaling, possibly through a mechanism which inhibits the potentially disease-promoting T2 response, is required for mice to confine the cryptococcal infection.

Animals↗

PubMed2004

Urease expression by Cryptococcus neoformans promotes microvascular sequestration, thereby enhancing central nervous system invasion.

Our objective was to determine the role of the cryptococcal virulence factor urease in pulmonary-to-central nervous system, dissemination, invasion, and growth. C. neoformans H99, the urease knockout strain (ure1) derived from H99, and the urease restored strain ure1+URE1-1 were used for the studies. The absence of cryptococcal urease (ure1infection) resulted in significant protection from the high mortality observed in H99-infected mice. All H99-infected mice had extremely high cryptococcal loads in their brains at the time of death, whereas only two of six animals that died of ure1 infection had detectable C. neoformans in the brain. Histological analysis of the blood-to-brain invasion by C. neoformans H99 demonstrated wedging of the yeasts in small capillaries, altered structure of microvessel walls, formation of mucoid cysts initiated in the proximity of damaged microcapillaries, and the absence of an inflammatory response. Direct inoculation of H99, ure1, and ure1+URE1-1 into the brain demonstrated that urease was not required to grow in the brain. However, the dissemination patterns in the brain, spleen, and other organs after intravenous inoculation indicated that cryptococcal urease contributes to the central nervous system invasion by enhancing yeast sequestration within microcapillary beds (such as within the brain) during hematogenous spread, thereby facilitating blood-to-brain invasion by C. neoformans.

Animals↗

PubMed2003

Leptin modulates neutrophil phagocytosis of Klebsiella pneumoniae.

Leptin is a pleiotropic hormone-cytokine known to regulate energy homeostasis and immune function. Neutrophils from leptin-deficient mice exhibited impaired phagocytosis of Klebsiella pneumoniae opsonized with serum containing complement and reduced CD11b expression that could be restored with exogenous leptin. These results suggest that leptin is required for normal neutrophil complement-mediated phagocytosis of bacteria.

Animals↗

PubMed2002

Urokinase-type plasminogen activator is required for the generation of a type 1 immune response to pulmonary Cryptococcus neoformans infection.

Urokinase-type plasminogen activator (uPA)(-/-) mice cannot mount protective host defenses during infection with the opportunistic yeast Cryptococcus neoformans (52D). Because effective host defense against C. neoformans requires specific immune responses and the generation of type 1 (T1) cytokines, we determined how the absence of uPA impacts these processes. Wild-type (WT) and uPA(-/-) mice were inoculated with C. neoformans. Macrophage antifungal activity was assessed histologically, T lymphocyte responses in vivo and proliferation in vitro were quantified, and cytokine concentrations were determined by ELISA. uPA(-/-) macrophages have impaired antimicrobial activity. Regional lymph nodes of infected uPA(-/-) mice contained fewer cells than WT, suggesting impaired T cell proliferation in response to the pathogen in vivo. In vitro, uPA(-/-) T lymphocytes had impaired proliferative responses to C. neoformans rechallenge compared with WT. Infected WT mice generated T1 cytokines in the lung, characterized by high levels of IFN-gamma and IL-12. uPA(-/-) mice had decreased levels of IFN-gamma and IL-12, and increased IL-5, a type 2 cytokine. In the absence of uPA, the cytokine profile of regional lymph nodes shifted from a T1 pattern characterized by IFN-gamma and IL-2 to a weak, nonpolarized response. We conclude that in the absence of uPA, lymphocyte proliferative responses are diminished, and mice fail to generate protective T1 cytokines, resulting in impaired antimicrobial activity. This study provides novel evidence that uPA is a critical modulator of immune responses and of immune cell effector functions in vivo.

Adoptive Transfer↗