Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shock.

Toll-like receptor-4 activation by lipopolysaccharide (LPS) induces the expression of interferon-beta (IFN-beta) in a MyD88-independent manner. Here we report that mice devoid of the JAK protein tyrosine kinase family member, Tyk2, were resistant to shock induced by high doses of LPS. Basal and LPS-induced expression of IFN-beta and IFN-alpha4 mRNA in Tyk2-null macrophages were diminished.

Expression of inducible nitric oxide synthase in skin lesions of patients with american cutaneous leishmaniasis.

Cytokine-inducible (or type 2) nitric oxide synthase (iNOS) is indispensable for the resolution of Leishmania major or Leishmania donovani infections in mice. In contrast, little is known about the expression and function of iNOS in human leishmaniasis. Here, we show by immunohistological analysis of skin biopsies from Mexican patients with local (LCL) or diffuse (DCL) cutaneous leishmaniasis that the expression of iNOS was most prominent in LCL lesions with small numbers of parasites whereas lesions with a high parasite burden (LCL or DCL) contained considerably fewer iNOS-positive cells.

Repetitive injections of dendritic cells matured with tumor necrosis factor alpha induce antigen-specific protection of mice from autoimmunity.

Mature dendritic cells (DCs) are believed to induce T cell immunity, whereas immature DCs induce T cell tolerance. Here we describe that injections of DCs matured with tumor necrosis factor (TNF)-alpha (TNF/DCs) induce antigen-specific protection from experimental autoimmune encephalomyelitis (EAE) in mice. Maturation by TNF-alpha induced high levels of major histocompatibility complex class II and costimulatory molecules on DCs, but they remained weak producers of proinflammatory cytokines.

Nitric oxide and the immune response.

During the past two decades, nitric oxide (NO) has been recognized as one of the most versatile players in the immune system. It is involved in the pathogenesis and control of infectious diseases, tumors, autoimmune processes and chronic degenerative diseases. Because of its variety of reaction partners (DNA, proteins, low-molecular weight thiols, prosthetic groups, reactive oxygen intermediates), its widespread production (by three different NO synthases (NOS) and the fact that its activity is strongly influenced by its concentration, NO continues to surprise and perplex immunologists.

IFN-gamma production by antigen-presenting cells: mechanisms emerge.

The suggestion that antigen-presenting cells (APCs) produce interferon gamma (IFN-gamma) is controversial because it conflicts with the initial paradigm in which the production of IFN-gamma was restricted to lymphoid cells. However, some answers to this skepticism have been provided by recent findings of high-level production and intracellular expression of IFN-gamma by interleukin-12 (IL-12)-stimulated macrophages and dendritic cells. New data are now emerging to explain the mechanism of production of IFN-gamma vby APCs.

Suppression of type 2 NO-synthase activity in macrophages by Candida albicans.

Macrophages (Mphi) are important for the defence against experimental disseminated candidiasis. Nitric oxide (NO) generated by the inducible isoform of NO-synthase (iNOS or NOS2) is thought to contribute to candidacidal effector functions by activated Mphi. In vitro, however, Mphi cannot control the growth and hyphal formation of Candida (C.

A case of aortic valve disease associated with Tropheryma whippelii infection in the absence of other signs of Whipple's disease.

A case of endocarditis caused by Tropheryma whippelii is reported. The 69-year-old patient was diagnosed as suffering from severe aortic regurgitation requiring aortic valve replacement, but showed no other symptoms of Whipple's disease. T.

Rapidly fatal leishmaniasis in resistant C57BL/6 mice lacking TNF.

The resolution of infections with the protozoan parasite Leishmania major in mice requires a Th1 response that is closely associated with the expression of IL-12, IFN-gamma, and inducible NO synthase. Previous Ab neutralization studies or the use of mice deficient for both TNF receptors suggested that TNF plays only a limited role in the control of parasite replication in vivo. In this study we demonstrate that resistant C57BL/6 (B6.

The production of IFN-gamma by IL-12/IL-18-activated macrophages requires STAT4 signaling and is inhibited by IL-4.

Macrophages release IFN-gamma on combined stimulation with IL-12 and IL-18, but the signaling requirements of this process and its regulation by other cytokines are unknown. Here, we demonstrate that STAT4 is indispensable for IL-12/IL-18-induced production of IFN-gamma by mouse peritoneal macrophages. Type 2 NO synthase (NOS2), which we previously found to be a prerequisite for IL-12-induced IFN-gamma production in NK cells, was not required for IFN-gamma production by these macrophages.

Visceral leishmaniasis in a German child who had never entered a known endemic area: case report and review of the literature.

We describe a case of visceral leishmaniasis in a 15-month-old German child. Diagnosis was significantly delayed because the patient had no history of travel to known endemic areas. Congenital or blood transfusion-associated leishmaniasis was ruled out.

Nitric oxide and the regulation of gene expression.

During the past 15 years, nitric oxide (NO) and NO synthases have become an important research topic in cellular and molecular biology. NO is produced by many if not all mammalian cells and fulfils a broad spectrum of signaling functions in physiological and pathophysiological processes. In this review, recent advances in our understanding of the mechanisms by which NO regulates the expression of eukaryotic genes will be summarized.

Partial impairment of cytokine responses in Tyk2-deficient mice.

To assess the role of the Janus kinase (Jak) family member Tyk2, we have generated Tyk2-/- mice. In contrast to other Jaks, where inactivation leads to a complete loss of the respective cytokine receptor signal, Tyk2-/- mice display reduced responses to IFNalpha/beta and IL-12 and a selective deficiency in Stat3 activation in these pathways. Unexpectedly, IFNgamma signaling is also impaired in Tyk2-/- mice.

[Leishmaniasis with cutaneous and visceral involvement in a 13-month old boy].

Leishmaniasis is an anthropozoonosis caused by infection with leishmania parasites with either cutaneous, mucosal or visceral (kala-azar) involvement. While the benign cutaneous form is self-limited death occurs in approximately 80% of children with kala-azar when untreated. The diagnosis of kala-azar should not be missed in children presenting with fever, hepatosplenomegaly and pancytopenia especially with a history of sand fly bites.

Regulation of type 2 nitric oxide synthase by type 1 interferons in macrophages infected with Leishmania major.

We recently reported that the infection of macrophages with Leishmania major led to the release of type 1 interferons (IFN-alpha /beta ). Moreover, at day 1 of infection of mice with L. major, IFN-alpha /beta was required for the expression of type 2 (inducible) NO synthase (NOS2 or iNOS) which, however, was restricted to a few macrophages in the dermis.

The function of type I interferons in antimicrobial immunity.

Type I interferons (IFN-alpha and IFN-beta) were originally described as potent antiviral substances, which are produced upon infection of animal cells with viruses. Despite a large body of literature that has accumulated during the past 25 years, their regulatory function in the immune system is still much less appreciated. Recent studies have highlighted the production of type I IFNs, their function in the immune response to infectious agents and the target cells of these interferons.

Fibroblasts as host cells in latent leishmaniosis.

Intracellular parasites are known to persist lifelong in mammalian hosts after the clinical cure of the disease, but the mechanisms of persistence are poorly understood. Here, we show by confocal laser microscopy that in the draining lymph nodes of mice that had healed a cutaneous infection with Leishmania major, 40% of the persisting parasites were associated with fibroblasts forming the reticular meshwork of the lymph nodes. In vitro, both promastigotes and amastigotes of L.

Leishmania-host-cell interaction: complexities and alternative views.

Leishmania are protozoan parasites that infect various mammalian species, including humans. It is generally thought that random attachment of the flagellated promastigotes to mononuclear phagocytes initiates their uptake via circumferential pseudopods. Intracellularly, the promastigotes become located in phagolysosomes in which they transform to and survive as 'aflagellated' amastigotes that hide their shortened flagellum within the flagellar pocket.

LPS induces apoptosis in macrophages mostly through the autocrine production of TNF-alpha.

The deleterious effects of lipopolysaccharide (LPS) during endotoxic shock are associated with the secretion of tumor necrosis factor (TNF) and the production of nitric oxide (NO), both predominantly released by tissue macrophages. We analyzed the mechanism by which LPS induces apoptosis in bone marrow-derived macrophages (BMDM). LPS-induced apoptosis reached a plateau at about 6 hours of stimulation, whereas the production of NO by the inducible NO-synthase (iNOS) required between 12 and 24 hours.

The role of nitric oxide in innate immunity.

Type 2 nitric oxide synthase (iNOS or NOS2) was originally described as an enzyme that is expressed in activated macrophages, generates nitric oxide (NO) from the amino acid L-arginine, and thereby contributes to the control of replication or killing of intracellular microbial pathogens. Since interferon (IFN)-gamma is the key cytokine for the induction of NOS2 in macrophages and the prototypic product of type 1 T-helper cells, high-level expression of NOS2 has been regarded to be mostly restricted to the adaptive phase of the immune response. In this review, we summarize data that demonstrate a prominent role of NOS2/NO also during innate immunity.

Reactive oxygen and reactive nitrogen intermediates in innate and specific immunity.

Nitric oxide, nitric oxide derivatives and reactive oxygen intermediates are toxic molecules of the immune system which contribute to the control of microbial pathogens and tumors. There is recent evidence for additional functions of these oxygen metabolites in innate and adaptive immunity; these functions include the modulation of the cytokine response of lymphocytes and the regulation of immune cell apoptosis, as well as immunodeviating effects. Components of several signal transduction pathways have been identified as intracellular targets for reactive nitrogen and oxygen intermediates.

Experimental murine leishmaniasis and the Th1/Th2 cell concept.

Herein, the current knowledge about the immune response during murine cutaneous leishmaniasis is summarized. Special regard is given to the characteristics and generation of Th1 and Th2 cells during this disease. Originally established on the basis of different cytokines produced by T cell clones, it is now known that the Th1/Th2 concept really defines totally different immune pathways that affect most, if not all cells of the immune system.

Human monocyte derived dendritic cells express functional P2X and P2Y receptors as well as ecto-nucleotidases.

We investigated the expression and function of P2 receptors and ecto-nucleotidases on human monocyte derived dendritic cells (DC). In addition we analyzed the effect of extracellular ATP on the maturation of DC. By RT-PCR, DC were found to express mRNA for several P2X (P2X1, P2X4, P2X5, P2X7) and P2Y (P2Y1, P2Y2, P2Y4, P2Y5, P2Y6, P2Y10, P2Y11) receptors.

Prevalence of Borrelia burgdorferi and granulocytic and monocytic ehrlichiae in Ixodes ricinus ticks from southern Germany.

A total of 287 adult Ixodes ricinus ticks, collected in two regions of southern Germany (Frankonia and Baden-Württemberg) where Borrelia burgdorferi infections are known to be endemic, were examined for the presence of 16S ribosomal DNA specific for the Ehrlichia phagocytophila genogroup, E. chaffeensis, E. canis, and B.