Michelle E Armstrong
Research interests
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InterestsTLRS, Inflammation, Fibrotic lung disease, Myofibroblasts, IL-17 Superfamily
Publications
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10.69Impact points
Macrophage Migration Inhibitory Factor Enzymatic Activity, Lung Inflammation and Cystic Fibrosis.
American journal of respiratory and critical care medicine. 05/2012;
RATIONALE: Macrophage migration inhibitory factor (MIF) is a pro-inflammatorymediator with unique tautomerase enzymatic activity; the precise function has notbeen clearly defined. We previously demonstrated that individual CF patients that are genetically predisposed to be high MIF producers develop... [more] RATIONALE: Macrophage migration inhibitory factor (MIF) is a pro-inflammatorymediator with unique tautomerase enzymatic activity; the precise function has notbeen clearly defined. We previously demonstrated that individual CF patients that are genetically predisposed to be high MIF producers develop accelerated end organ injury. OBJECTIVES: To characterize the effects of the MIF-CATT polymorphism in CFpatients ex vivo. To investigate the role of MIF's tautomerase activity in a murinemodel of Pseudomonas aeruginosa infection. METHODS: MIF and TNF-α protein levels were assessed in plasma or PBMCsupernatants by ELISA. A murine pulmonary model of chronic Pseudomonasinfection was utilized in MIF wild-type mice (mif+/+) and in tautomerase-null, MIFgene knock-in mice (mif P1G/P1G). MEASUREMENTS: MIF protein was measured in plasma and PBMCs from 5- and 6-CATT CF patients; LPS-induced TNF-α production from PBMCs was also assessed.The effect of a specific inhibitor of MIF-tautomerase activity, ISO-1, was investigated in PBMCs. In the murine infection model, total weight loss, differential cell counts, bacterial load and intra-acinar airspace/tissue volume was measured. RESULTS: MIF and TNF-α levels were increased in 6-CATT compared with 5-CATTCF patients. LPS-induced TNF-α production from PBMCs was attenuated in thepresence of ISO-1. In a murine model of Pseudomonas infection, significantly lesspulmonary inflammation and bacterial load was observed in mif P1G/P1G compared with mif+/+ mice. CONCLUSIONS: MIF-tautomerase activity may provide a novel therapeutic target inpatients with chronic inflammatory diseases such as CF, particularly those patientswho are genetically predisposed to produce increased levels of this cytokine.
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Blood pressure and TNF-α act synergistically to increase leucocyte CD11b adhesion molecule expression in the BELFAST study: implications for better blood pressure control in ageing.
Age (Dordrecht, Netherlands). 11/2011;
Hypertension, a key risk factor for stroke, cardiovascular disease and dementia, is associated with chronic vascular inflammation, and although poorly understood, putative mechanisms include pro-inflammatory responses induced by mechanical stretching, with cytokine release and associated up-regulate... [more] Hypertension, a key risk factor for stroke, cardiovascular disease and dementia, is associated with chronic vascular inflammation, and although poorly understood, putative mechanisms include pro-inflammatory responses induced by mechanical stretching, with cytokine release and associated up-regulated expression of adhesion molecules. Because blood pressure increases with age, we measured baseline and tumour necrosis alpha (TNF-α)-stimulated CD11b/CD18 adhesion molecule expression on leucocytes to assess any association between the two. In 38 subjects (mean age 85 years), consecutively enrolled from Belfast Elderly Longitudinal Free-Living Aging Study (BELFAST), baseline and TNF-α-stimulated CD11b/CD18 expression on separated monocytes and neutrophils increased with systolic blood pressure >120 mmHg (p = 0.05) and for lymphocytes, with diastolic blood pressure >80 mmHg (p < 0.05).These findings show increased potential stickiness of intravascular cells with increasing blood pressure which is accentuated by TNF-α, and suggest mechanistic reasons why better hypertension control is important.
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0.91Impact points
Macrophage migration inhibitory factor (MIF), enzymatic activity and the inflammatory response.
BioFactors (Oxford, England). 04/2009;
Macrophage migration inhibitory factor represents a key cytokine in human diseases. It plays an important role in both innate and acquired immunity and has been shown to be a key mediator of inflammatory diseases. More recently MIF has been implicated in cancer pathogenesis. Over the decades its str... [more] Macrophage migration inhibitory factor represents a key cytokine in human diseases. It plays an important role in both innate and acquired immunity and has been shown to be a key mediator of inflammatory diseases. More recently MIF has been implicated in cancer pathogenesis. Over the decades its structure and functions have been elucidated and this has led to it being further classified as a hormone and an enzyme. It has isomerase enzymatic activity and increasing evidence implicates this activity in inflammatory disease. Consequently, there is increasing interest in developing small molecular weight inhibitors which could target this novel enzymatic activity in disease. (c) 2009 International Union of Biochemistry and Molecular Biology, Inc.
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4.00Impact points
IL-1F5 mediates anti-inflammatory activity in the brain through induction of IL-4 following interaction with SIGIRR/TIR8.
Journal of neurochemistry. 07/2008; 105(5):1960-9.
Similarity in structure and sequence homology has led to the identification of new members of the interleukin-1 (IL-1) ligand and receptor superfamilies. IL-1F6, IL-1F8 and IL-1F9 have been shown to signal through IL-1R-related protein 2 and IL-1 receptor accessory protein leading to activation of N... [more] Similarity in structure and sequence homology has led to the identification of new members of the interleukin-1 (IL-1) ligand and receptor superfamilies. IL-1F6, IL-1F8 and IL-1F9 have been shown to signal through IL-1R-related protein 2 and IL-1 receptor accessory protein leading to activation of NFkappaB, while IL-1F7 and IL-1F10 interact with the IL-18 receptor and the soluble IL-1 receptor type I respectively. In contrast, identification of a biological role for IL-1F5 has remained elusive, with conflicting data relating to its possible ability to antagonize IL-1F9-stimulated activation of NFkappaB in Jurkat cells transfected with IL-1R-related protein 2. In this study, we set out to investigate a possible role for IL-1F5 in the brain and report that it antagonizes the inflammatory effects of IL-1beta and lipopolysaccharide (LPS) in vivo and in vitro including the inhibitory effect on long-term potentiation (LTP) in rat hippocampus. We demonstrate that IL-1F5 induces IL-4 mRNA and protein expression in glia in vitro and enhances hippocampal expression of IL-4 following intracerebroventricular (i.c.v.) injection. The inhibitory effect of IL-1F5 on LPS-induced IL-1beta is attenuated in cells from IL-4-defective (IL-4-/- mice). Our findings suggest that IL-1F5 mediates anti-inflammatory effects through its ability to induce IL-4 production and that this is a consequence of its interaction with the orphan receptor, single Ig IL-1R-related molecule (SIGIRR)/TIR8, as the effects were not observed in SIGIRR-/- mice. In contrast to its effects in brain tissue, IL-1F5 did not attenuate LPS-induced changes, or up-regulated IL-4 in macrophages or dendritic cells, suggesting that the effect is confined to the brain.
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5.65Impact points
Small interfering RNAs induce macrophage migration inhibitory factor production and proliferation in breast cancer cells via a double-stranded RNA-dependent protein kinase-dependent mechanism.
Journal of immunology (Baltimore, Md. : 1950). 06/2008; 180(11):7125-33.
Small interfering RNAs (siRNAs) represent a novel tool to induce gene silencing in mammalian cells and clinical trials are currently ongoing to assess the therapeutic efficacy of siRNAs in various human diseases, including age-related macular degeneration and respiratory syncytial virus infection. H... [more] Small interfering RNAs (siRNAs) represent a novel tool to induce gene silencing in mammalian cells and clinical trials are currently ongoing to assess the therapeutic efficacy of siRNAs in various human diseases, including age-related macular degeneration and respiratory syncytial virus infection. However, previously reported off-target, nonspecific effects of siRNAs, including activation of type I IFNs and proinflammatory cytokines, remain an outstanding concern regarding use of these agents in vivo. Macrophage-migration inhibitory factor (MIF) is a pleiotropic cytokine with well-described roles in cell proliferation, tumorigenesis, and angiogenesis and represents a target gene for siRNA-based therapy in the treatment of breast cancer. However, in this study we describe an increase in MIF production from mammary adenocarcinoma (MCF-7) cells following transfection with MIF siRNA and various control siRNAs. This effect was shown to be dose-dependent and was attenuated in the presence of a double-stranded RNA-dependent protein kinase inhibitor, 2-aminopurine. Furthermore, treatment of MCF-7 cells with poly(I:C) also stimulated a PKR-dependent increase in MIF production from MCF-7 cells. The biological consequence of the siRNA-induced increase in MIF production from MCF-7 cells was a PKR-dependent increase in proliferation of breast cancer cells. Furthermore, in cDNAs prepared from a primary human breast cancer cohort, we demonstrated a significant correlation (Spearman rank correlation coefficient, r = 0.50, p < 0.0001, n = 63) between PKR- and MIF-mRNA expression. In conclusion, this study highlights the potential biological consequences of off-target, nonspecific effects of siRNAs and underlines the safety concerns regarding the use of siRNAs in the treatment of human diseases, such as cancer.
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5.87Impact points
Proinflammatory responses in the murine brain after intranasal delivery of cholera toxin: implications for the use of AB toxins as adjuvants in intranasal vaccines.
The Journal of infectious diseases. 12/2005; 192(9):1628-33.
Intranasal delivery of vaccines provides an attractive alternative to parenteral delivery, but it requires appropriate mucosal adjuvants. Cholera toxin (CT) is a powerful mucosal adjuvant, but it can undergo retrograde transport to the brain via the olfactory system after intranasal delivery. We dem... [more] Intranasal delivery of vaccines provides an attractive alternative to parenteral delivery, but it requires appropriate mucosal adjuvants. Cholera toxin (CT) is a powerful mucosal adjuvant, but it can undergo retrograde transport to the brain via the olfactory system after intranasal delivery. We demonstrate that intranasal delivery of CT increases the expression of interleukin-1 beta , cyclooxygenase-2, and chemokine messenger RNA in the murine hypothalamus, whereas parenterally delivered CT has little effect. Our findings suggest that CT can induce proinflammatory mediators in the brain when it is administered intranasally but not parenterally, and they raise concerns about the use of AB toxins as adjuvants in intranasal vaccines.
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4.40Impact points
Effects of cholera toxin on innate and adaptive immunity and its application as an immunomodulatory agent.
Journal of leukocyte biology. 06/2004; 75(5):756-63.
Cholera toxin (CT) is a potent vaccine adjuvant when administered via parenteral, mucosal, or transcutaneous routes. It also inhibits innate inflammatory responses induced by pathogen-derived molecules, such as lipopolysaccharide (LPS). We demonstrated previously that CT promotes the induction of re... [more] Cholera toxin (CT) is a potent vaccine adjuvant when administered via parenteral, mucosal, or transcutaneous routes. It also inhibits innate inflammatory responses induced by pathogen-derived molecules, such as lipopolysaccharide (LPS). We demonstrated previously that CT promotes the induction of regulatory type 1 T cells (Tr1) as well as T helper type 2 cells (Th2). T cells from mice immunized with antigen in the presence of CT produced high levels of interleukin (IL)-10 and IL-5 and low levels of IL-4 and interferon-gamma (IFN-gamma). Here, we demonstrate that immunization with antigen in the presence of CT induced a population of antigen-specific CD4(+) T cells that produced IL-10 in the absence of IL-4, in addition to cells that coexpressed IL-4 and IL-10 or produced IL-4 only. CT-generated Tr1 cells inhibited antigen-specific proliferation as well as IFN-gamma production by Th1 cells, and this suppression was cell contact-independent. It is interesting that coincubation with Th1 cells significantly enhanced IL-10 production by the Tr1 cells. As IL-10 can promote the differentiation of Tr1 cells, we investigated cytokine production by dendritic cells (DC) following exposure to CT. Previous data showed that CT can modulate the expression of costimulatory molecules and inhibit the production of chemokines and cytokines, including IL-12 and tumor necrosis factor alpha and enhance IL-10 production. Here, we show that CT synergizes with LPS to induce IL-6 and IL-1beta in addition to IL-10 production by immature DC. Therefore, CT may promote the induction of Th2 and Tr1 cells in part via selective modulation of DC cytokine production and costimulatory molecule expression.
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5.65Impact points
Cholera toxin promotes the induction of regulatory T cells specific for bystander antigens by modulating dendritic cell activation.
Journal of immunology (Baltimore, Md. : 1950). 10/2003; 171(5):2384-92.
It has previously been reported that cholera toxin (CT) is a potent mucosal adjuvant that enhances Th2 or mixed Th1/Th2 type responses to coadministered foreign Ag. Here we demonstrate that CT also promotes the generation of regulatory T (Tr) cells against bystander Ag. Parenteral immunization of mi... [more] It has previously been reported that cholera toxin (CT) is a potent mucosal adjuvant that enhances Th2 or mixed Th1/Th2 type responses to coadministered foreign Ag. Here we demonstrate that CT also promotes the generation of regulatory T (Tr) cells against bystander Ag. Parenteral immunization of mice with Ag in the presence of CT induced T cells that secreted high levels of IL-4 and IL-10 and lower levels of IL-5 and IFN-gamma. Ag-specific CD4(+) T cell lines and clones generated from these mice had cytokine profiles characteristic of Th2 or type 1 Tr cells, and these T cells suppressed IFN-gamma production by Th1 cells. Furthermore, adoptive transfer of bone marrow-derived dendritic cells (DC) incubated with Ag and CT induced T cells that secreted IL-4 and IL-10 and low concentrations of IL-5. It has previously been shown that IL-10 promotes the differentiation or expansion of type 1 Tr cells. Here we found that CT synergized with low doses of LPS to induce IL-10 production by immature DC. CT also enhanced the expression of CD80, CD86, and OX40 (CD134) on DC and induced the secretion of the chemokine, macrophage inflammatory protein-2 (MIP-2), but inhibited LPS-driven induction of CD40 and ICAM-I expression and production of the inflammatory cytokines/chemokines IL-12, TNF-alpha, MIP-1alpha, MIP-1beta, and monocyte chemoattractant protein-1. Our findings suggest that CT induces maturation of DC, but, by inducing IL-10, inhibiting IL-12, and selectively affecting surface marker expression, suppresses the generation of Th1 cells and promotes the induction of T cells with regulatory activity.
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2.84Impact points
IL-1beta-dependent neurological effects of the whole cell pertussis vaccine: a role for IL-1-associated signalling components in vaccine reactogenicity.
Journal of neuroimmunology. 04/2003; 136(1-2):25-33.
Immunization with the whole cell pertussis vaccine (Pw), but not the acellular pertussis vaccine (Pa), is associated with a number of neurological side effects. Previously, we have demonstrated a role for interleukin-1beta (IL-1beta) in Pw reactogenicity. Here we report that parenteral Pw administra... [more] Immunization with the whole cell pertussis vaccine (Pw), but not the acellular pertussis vaccine (Pa), is associated with a number of neurological side effects. Previously, we have demonstrated a role for interleukin-1beta (IL-1beta) in Pw reactogenicity. Here we report that parenteral Pw administration resulted in a concomitant increase IL-1 type I receptor (IL-1RI) mRNA and a decrease in IL-1 type II receptor (IL-1RII) mRNA expression in the murine hypothalamus. These Pw-induced changes were accompanied by an increase in caspase-1 and interleukin-1beta (IL-1beta), and were associated with increased activity of the stress-activated kinase, p38. In contrast, immunization with Pa failed to activate pro-inflammatory IL-1 responses but resulted in increased IL-1 receptor antagonist (IL-1ra) production. These results suggest that the neurological effects of Pw are associated with central activation of IL-1beta and IL-1-associated signalling components.
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1.66Impact points
Age-related alterations in basal expression and in vitro, tumour necrosis factor alpha mediated, upregulation of CD11b.
Gerontology. 47(4):180-5.
BACKGROUND: The beta(2-)integrin CD11b (Mac-1) plays a crucial role in the firm attachment of leucocytes to the endothelium during the inflammatory response. OBJECTIVE: This study aimed to determine whether the increased incidence of infections witnessed in elderly individuals compared to their youn... [more] BACKGROUND: The beta(2-)integrin CD11b (Mac-1) plays a crucial role in the firm attachment of leucocytes to the endothelium during the inflammatory response. OBJECTIVE: This study aimed to determine whether the increased incidence of infections witnessed in elderly individuals compared to their younger counterparts was associated with deficiencies in basal expression and/or upregulation of CD11b. METHODS: Flow cytometry was used to measure CD11b expression, before and after in vitro tumour necrosis factor alpha (TNF-alpha) stimulation, on neutrophils, monocytes and lymphocytes from healthy volunteers aged less than 36 years and Senieur-approximated 70-85 and over 85 year olds. The TNF-alpha levels in serum were measured using a commercially available enzyme-linked immunoassay technique. RESULTS: The basal expression of CD11b on monocytes and lymphocytes was highest in the 70-85-year-olds and lowest in the > 85-year-olds. Following in vitro stimulation using low (10 IU) and high (100 IU) TNF-alpha concentrations, subjects > 85 years consistently showed significantly lower increases in CD11b expression on each of the three cell types. The maximal increase in CD11b expression was in the 70-85-year age group for neutrophils and monocytes and in < 36-year-olds for lymphocytes. Serum TNF-alpha was significantly higher in the elderly groups. Regression analysis showed a significant association between TNF-alpha and expression of CD11b on lymphocytes before and after TNF-alpha stimulation and for neutrophils before stimulation. CONCLUSIONS: The results of this study suggest that CD11b expression on leucocytes may not be consistent throughout life. Such age-related changes could compromise the inflammatory response, rendering individuals > 85 years old more susceptible to infections. Alternatively, the lower levels of CD11b expression in this group may represent downregulation and protection against excess leucocyte activation within the vascular system and may, therefore, provide a mechanism for successful ageing.
Following (3)
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John Baugh
University College Dublin -
Gordon Cooke
University College Dublin -
Ed C Lavelle
Trinity College, Dublin
Topics (5)
