Biomedical subjects

Ineke Verschueren

Publications and source records attributed to Ineke Verschueren.

8 recordsLinked to original sources

PubMed2006

Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance.

Here we report the presence of hyperphagia, obesity and insulin resistance in knockout mice deficient in IL-18 or IL-18 receptor, and in mice transgenic for expression of IL-18 binding protein. Obesity of Il18-/- mice resulted from accumulation of fat tissue based on increased food intake. Il18-/- mice also had hyperinsulinemia, consistent with insulin resistance and hyperglycemia. Insulin resistance was secondary to obesity induced by increased food intake and occurred at the liver level as well as at the muscle and fat-tissue level. The molecular mechanisms responsible for the hepatic insulin resistance in the Il18-/- mice involved an enhanced expression of genes associated with gluconeogenesis in the liver of Il18-/- mice, resulting from defective phosphorylation of STAT3. Recombinant IL-18 (rIL-18) administered intracerebrally inhibited food intake. In addition, rIL-18 reversed hyperglycemia in Il18-/- mice through activation of STAT3 phosphorylation. These findings indicate a new role of IL-18 in the homeostasis of energy intake and insulin sensitivity.

Animals↗

PubMed2005

Differential cytokine production and Toll-like receptor signaling pathways by Candida albicans blastoconidia and hyphae.

Toll-like receptors (TLR) are crucial for an efficient antifungal defense. We investigated the differential recognition of blastoconidia and hyphae of Candida albicans by TLRs. In contrast to Candida blastoconidia, which stimulated large amounts of gamma interferon (IFN-gamma), the tissue-invasive Candida hyphae did not stimulate any IFN-gamma by human peripheral blood mononuclear cells (PBMC) or murine splenic lymphocytes. After stimulation with blastoconidia, the production of IFN-gamma was TLR4 dependent, as shown by the significantly decreased IFN-gamma production in anti-TLR4-treated PBMC and in splenic lymphocytes from TLR4-defective ScCr mice. In addition, peritoneal macrophages from ScCr mice produced less tumor necrosis factor alpha (TNF-alpha) than macrophages of control mice did when stimulated with Candida blastoconidia, but not with hyphae, indicating that TLR4-mediated signals are lost during hyphal germination. In contrast, macrophages from TLR2 knockout mice had a decreased production of TNF-alpha in response to both Candida blastoconidia and hyphae. Candida hyphae stimulated production of interleukin-10 through TLR2-dependent mechanisms. In conclusion, TLR4 mediates proinflammatory cytokine induction after Candida stimulation, whereas Candida recognition by TLR2 leads mainly to anti-inflammatory cytokine release. TLR4-mediated proinflammatory signals are lost during germination of Candida blastoconidia into hyphae. Phenotypic switching during germination may be an important escape mechanism of C. albicans, resulting in counteracting host defense.

Animals↗

PubMed2005

Interleukin-18 does not modulate the acute-phase response.

IL-18 is a pro-inflammatory cytokine of the IL-1 family and it induces IL-1, TNF, and IL-6, all of which are endogenous pyrogens. The pyrogenic properties of recombinant IL-18 were studied in a rabbit model of fever. rIL-18 did not cause fever when injected intravenously into rabbits. Furthermore, the ability of rIL-18 to modulate other components of the acute-phase response was assessed. rIL-18 did not induce leukocytosis, or changes of circulating concentrations of lipoproteins and corticosterone in mice. In conclusion, rIL-18 is not able to induce a febrile response in rabbits and does not modulate the acute-phase response in mice.

Acute-Phase Reaction↗

PubMed2004

Human dendritic cells are less potent at killing Candida albicans than both monocytes and macrophages.

Dendritic cells (DC) function as professional phagocytes to kill Candida albicans and subsequently present it to the adaptive immune system. Monocytes, macrophages and DC were generated from five individual donors and their Candida-killing capacity and cytokine release were assessed. Compared to monocytes and macrophages, DC from healthy volunteers were significantly less effective in C. albicans--stimulated cytokine release, killing of C. albicans blastoconidia and damaging of C. albicans hyphae. In conclusion, while important as antigen-presenting cells and initiators of the adaptive immune system, DC are poor in both intracellular killing and damaging of C. albicans hyphae. Effective handling of large numbers of C. albicans is the prime task of the innate immune system consisting of large numbers of neutrophils and monocytes.

Candida albicans↗

PubMed2003

Differential role of IL-18 and IL-12 in the host defense against disseminated Candida albicans infection.

IFN-gamma plays a crucial role in the defense against infection with Candida albicans. Since IL-18 and IL-12 are strong stimuli of IFN-gamma production, we investigated whether endogenous IL-18 and IL-12 are involved in the host defense during disseminated candidiasis. IL-18 knockout (IL-18-/-) mice, but not IL-12-/- mice, displayed an increased mortality due to C. albicans infection, accompanied by a decreased clearance of the yeasts from the kidneys late during the course of infection. Histopathology of the organs, combined with phagocyte recruitment experiments, showed a decreased influx of monocytes at the sites of Candida infection, mainly in the IL-18-/- mice. Whereas production of the chemokine KC was decreased in both IL-18-/- and IL-12-/- mice, MIP-2 production was deficient only in IL-18-/- animals, which may explain the differences in phagocyte recruitment. In addition, although IFN-gamma production capacity, as a parameter of the Th1-protective immunity, was reduced by 65 to 80% in the IL-12-/- mice, this defect was even more pronounced in the IL-18-/- mice (85 to 95% down-modulation). In conclusion, the anticandidal effects of endogenous IL-18 are mediated late during the infection by assuring a proper IFN-gamma response and promoting the infiltration of the site of infection by monocytes.

Animals↗

PubMed2002

The role of toll-like receptor (TLR) 2 and TLR4 in the host defense against disseminated candidiasis.

Toll-like receptors (TLRs) represent the main class of pattern-recognition receptors involved in sensing pathogenic microorganisms. The aim of the present study was to assess the role of TLR4 in the defense against Candida albicans infection. The outgrowth of C. albicans was 10-fold higher in TLR4-defective C3H/HeJ mice, compared with that in control C3H/HeN mice (P<.05). Production of tumor necrosis factor (TNF) and interleukin (IL)-1alpha and IL-1beta by mouse macrophages in response to C. albicans stimulation was not affected by TLR4, and the candidacidal capacities of the neutrophils and macrophages of C3H/HeJ mice were normal. In contrast, production of the CXC chemokines KC and macrophage inhibitory protein-2 was 40%-60% lower by the macrophages of C3H/HeJ mice (P<.05), which resulted in a 40% decrease in neutrophil recruitment to the site of infection. Candida-induced TNF and IL-1beta production by human peripheral blood mononuclear cells was significantly inhibited by blocking anti-TLR2 antibodies in vitro. In conclusion, TLR4-defective C3H/HeJ mice are more susceptible to C. albicans infection, and this is associated with impaired chemokine expression and neutrophil recruitment.

Animals↗

PubMed2002

CD40/CD40 ligand interactions in the host defense against disseminated Candida albicans infection: the role of macrophage-derived nitric oxide.

CD40L interaction with CD40 is required for normal cellular immune responses such as T cell-mediated activation of monocytes/macrophages, proinflammatory cytokine production, and leukocyte extravasation. We investigated the role of CD40/CD40 ligand (L) interactions during disseminated candidiasis in CD40L knockout (CD40L-/-) mice. While early during infection there were no differences in the Candida albicans outgrowth in the organs of wild-type and knockout mice, the CD40L-/- mice had a significantly increased yeast load in the kidneys compared to CD40L+/+ mice late during infection. Similar effects were observed in CD40L+/+ mice in which CD40 ligation was blocked by a neutralizing anti-CD40 antibody. The peak TNF-alpha plasma concentrations were significantly lower in the CD40L-/- mice than in CD40L+/+ mice. C. albicans-stimulated production of nitric oxide (NO) by peritoneal macrophages from CD40L-/- in vitro was significantly lower than that of control mice, and this was responsible for a reduced candidacidal activity of CD40L-/- macrophages. The role of endogenous NO synthesis induced by CD40 ligation for the defense against disseminated candidiasis was further demonstrated by the absence of these effects in knockout mice deficient in inducible NO-synthase. In conclusion, absence of CD40/CD40L interactions results in increased susceptibility to disseminated infection with C. albicans through decreased NO-dependent killing of Candida by macrophages.

Animals↗

PubMed2002

Role of interleukin-18 in host defense against disseminated Candida albicans infection.

In mice injected intravenously with Candida albicans, administration of anti-interleukin-18 (IL-18) antibodies increased the yeast load in the kidneys. There was no effect on the organ load with Candida when gamma interferon (IFN-gamma)-deficient mice were treated with anti-IL-18 antibodies, suggesting that the protective effect of IL-18 is mediated through endogenous IFN-gamma.

Animals↗