Marina Freudenberg

Bio: Marina Freudenberg is an academic researcher from University of Texas Southwestern Medical Center. The author has contributed to research in topics: Cancer & TLR4. The author has an hindex of 4, co-authored 6 publications receiving 14423 citations.

Defective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in Tlr4 Gene

Abstract: Mutations of the gene Lps selectively impede lipopolysaccharide (LPS) signal transduction in C3H/HeJ and C57BL/10ScCr mice, rendering them resistant to endotoxin yet highly susceptible to Gram-negative infection. The codominant Lpsd allele of C3H/HeJ mice was shown to correspond to a missense mutation in the third exon of the Toll-like receptor-4 gene (Tlr4), predicted to replace proline with histidine at position 712 of the polypeptide chain. C57BL/10ScCr mice are homozygous for a null mutation of Tlr4. Thus, the mammalian Tlr4 protein has been adapted primarily to subserve the recognition of LPS and presumably transduces the LPS signal across the plasma membrane. Destructive mutations of Tlr4 predispose to the development of Gram-negative sepsis, leaving most aspects of immune function intact.

Leishmania major infection in C57BL/10 mice differing at the Lps locus: a new non-healing phenotype ORIGINAL INVESTIGA T ION

Abstract: The course of cutaneous leishmaniasis was ex- amined in mice from two genetically closely related strains, C57BL/10ScCr (Cr) and C57BL/10ScSn (Sn). Sn mice are able to heal Leishmania majorinfections, while Cr mice are unable to heal. The cutaneous lesions of the Cr mice progressed continuously and the increase in lesion size was paralleled by an unrestricted growth of the para- sites in vivo. Cr mice, in contrast to their Sn counterparts, are highly resistant to all effects of lipopolysaccharide (LPS). The nonhealing L. major infection in Cr mice is in sharp contrast to the course of infection in another endo- toxin-nonresponder mouse strain, C3H/HeJ, which heal in- fections with L. major. Cr mice exhibit, in addition to the defective LPS responsiveness, an impaired interferon- γ (IFN-γ) response after infection with a variety of microor- ganisms. The insufficient activation of parasitized macro- phages to kill intracellular L. major could be due to the in- ability of splenocytes from infected Cr mice to secrete IFN-γ upon restimulation with L. major. IFN-γ is essen- tial for the efficient activation of parasitized macrophages to kill intracellular L. major by producing nitric oxide (NO). Although bone marrow-derived Cr macrophages do not produce NO in response to LPS, both Sn and Cr mac-

Method for the generation of non-transformed macrophage cell lines

Abstract: The present invention relates to a method for producing self-renewing, non-transformed macrophages comprising: culturing a cell preparation obtained from an organ obtained from a mammal in culture medium to which granulocyte macrophage colony-stimulating factor (GM- CSF) has been added; thereby differentiating the cell population into self-renewing, non- transformed macrophages. The present invention further relates to macrophages obtainable by the method of the invention as well as their use in medicine or medical/pharmaceutical research. Furthermore, the present invention relates to a method of identifying a compound having a pharmacological, differentiating, proliferative or anti-proliferative, cytotoxic or transforming effect on the self-renewing, non-transformed macrophages of the invention as well as a method of identifying a compound capable of treating a disease selected from the group consisting of an inflammatory disease, infections, asthma, contact allergies as well as the side effects associated with virus vector gene-therapy.

Compounds leading to an increase of the IL-12/IL-10 ratio and their use for therapy of infectious and proliferative diseases

Abstract: Described is the treatment of immunologically relevant diseases such as infections or a proliferative disease, in particular cancer, by increasing the IL-12/IL-10 ratio caused by the sequential administration of lipopeptides (e.g., FSL-1, FSL-2 or OspA-Lp) and lipopolysaccharides (e.g., LPS R60) alone or in combination with IFN-γ.

Innate Immune Recognition

Abstract: ▪ Abstract The innate immune system is a universal and ancient form of host defense against infection. Innate immune recognition relies on a limited number of germline-encoded receptors. These receptors evolved to recognize conserved products of microbial metabolism produced by microbial pathogens, but not by the host. Recognition of these molecular structures allows the immune system to distinguish infectious nonself from noninfectious self. Toll-like receptors play a major role in pathogen recognition and initiation of inflammatory and immune responses. Stimulation of Toll-like receptors by microbial products leads to the activation of signaling pathways that result in the induction of antimicrobial genes and inflammatory cytokines. In addition, stimulation of Toll-like receptors triggers dendritic cell maturation and results in the induction of costimulatory molecules and increased antigen-presenting capacity. Thus, microbial recognition by Toll-like receptors helps to direct adaptive immune responses ...

Toll-like receptor signalling

Abstract: One of the mechanisms by which the innate immune system senses the invasion of pathogenic microorganisms is through the Toll-like receptors (TLRs), which recognize specific molecular patterns that are present in microbial components. Stimulation of different TLRs induces distinct patterns of gene expression, which not only leads to the activation of innate immunity but also instructs the development of antigen-specific acquired immunity. Here, we review the rapid progress that has recently improved our understanding of the molecular mechanisms that mediate TLR signalling.

A Toll-like receptor recognizes bacterial DNA.

Abstract: DNA from bacteria has stimulatory effects on mammalian immune cells, which depend on the presence of unmethylated CpG dinucleotides in the bacterial DNA. In contrast, mammalian DNA has a low frequency of CpG dinucleotides, and these are mostly methylated; therefore, mammalian DNA does not have immuno-stimulatory activity. CpG DNA induces a strong T-helper-1-like inflammatory response. Accumulating evidence has revealed the therapeutic potential of CpG DNA as adjuvants for vaccination strategies for cancer, allergy and infectious diseases. Despite its promising clinical use, the molecular mechanism by which CpG DNA activates immune cells remains unclear. Here we show that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9. TLR9-deficient (TLR9-/-) mice did not show any response to CpG DNA, including proliferation of splenocytes, inflammatory cytokine production from macrophages and maturation of dendritic cells. TLR9-/- mice showed resistance to the lethal effect of CpG DNA without any elevation of serum pro-inflammatory cytokine levels. The in vivo CpG-DNA-mediated T-helper type-1 response was also abolished in TLR9-/- mice. Thus, vertebrate immune systems appear to have evolved a specific Toll-like receptor that distinguishes bacterial DNA from self-DNA.

Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3.

Abstract: Toll-like receptors (TLRs) are a family of innate immune-recognition receptors that recognize molecular patterns associated with microbial pathogens, and induce antimicrobial immune responses. Double-stranded RNA (dsRNA) is a molecular pattern associated with viral infection, because it is produced by most viruses at some point during their replication. Here we show that mammalian TLR3 recognizes dsRNA, and that activation of the receptor induces the activation of NF-kappaB and the production of type I interferons (IFNs). TLR3-deficient (TLR3-/-) mice showed reduced responses to polyinosine-polycytidylic acid (poly(I:C)), resistance to the lethal effect of poly(I:C) when sensitized with d-galactosamine (d-GalN), and reduced production of inflammatory cytokines. MyD88 is an adaptor protein that is shared by all the known TLRs. When activated by poly(I:C), TLR3 induces cytokine production through a signalling pathway dependent on MyD88. Moreover, poly(I:C) can induce activation of NF-kappaB and mitogen-activated protein (MAP) kinases independently of MyD88, and cause dendritic cells to mature.