Triacyl-lipopentapeptide adjuvants: TLR2-dependent activation of macrophages and modulation of receptor-mediated cell activation by altering acyl-moieties

Müller, Silke D.C; Müller, Markus; Huber, Maria; Esche, Ulrich vor dem; Kirschning, Carsten J.; Wagner, Hermann; Bessler, Wolfgang G.; Mittenbühler, K

doi:10.1016/j.intimp.2004.04.012

Cited by 19 publications

(24 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The stimulation by LPS and PAM 3 CSK 4 when added at concentrations of 10 ng/ml, 100 ng/ml, and 1,000 ng/ml was measured, and the optimal concentration for stimulating TNF-␣ production in C57BL/6J BMDMs was found to be 100 ng/ml for both agonists (data not shown). This result is in agreement with previously published studies (7,17,21,22,24,25). Therefore, for subsequent experiments, we used 100 ng/ml for LPS and PAM 3 CSK 4 .…”

Section: Resultssupporting

confidence: 91%

“…All transfections also contained phRLTK (Promega) as an internal control for transfection efficiency. HEK293 cells were transfected in triplicate wells in a 24-well plate and then exposed 48 h after transfection to vehicle control, PGN (10 g/ml) (21,22), PAM 3 CSK 4 (100 ng/ml) (24,25), purified LPS (100 ng/ml or 1 g/ml) (7), or HKBa (OD 600 of 0.4) (17). Transfected cells were challenged for 6 h, and luciferase activity was measured using the dual luciferase assay (Promega).…”

mentioning

confidence: 99%

See 1 more Smart Citation

MyD88-Dependent Signaling Contributes to Protection following Bacillus anthracis Spore Challenge of Mice: Implications for Toll-Like Receptor Signaling

et al. 2005

View full text Add to dashboard Cite

Bacillus anthracis is a spore-forming, gram-positive organism that is the causative agent of the disease anthrax. Recognition of Bacillus anthracis by the host innate immune system likely plays a key protective role following infection. In the present study, we examined the role of TLR2, TLR4, and MyD88 in the response to B. anthracis. Heat-killed Bacillus anthracis stimulated TLR2, but not TLR4, signaling in HEK293 cells and stimulated tumor necrosis factor alpha (TNF-␣) production in C3H/HeN, C3H/HeJ, and C57BL/6J bone marrow-derived macrophages. The ability of heat-killed B. anthracis to induce a TNF-␣ response was preserved in TLR2؊/؊ but not in MyD88 ؊/؊ macrophages. In vivo studies revealed that TLR2 ؊/؊ mice and TLR4-deficient mice were resistant to challenge with aerosolized Sterne strain spores but MyD88 ؊/؊ mice were as susceptible as A/J mice. We conclude that, although recognition of B. anthracis occurs via TLR2, additional MyD88-dependent pathways contribute to the host innate immune response to anthrax infection.

show abstract

Section: Resultssupporting

confidence: 91%

mentioning

confidence: 99%

MyD88-Dependent Signaling Contributes to Protection following Bacillus anthracis Spore Challenge of Mice: Implications for Toll-Like Receptor Signaling

et al. 2005

View full text Add to dashboard Cite

show abstract

“…The critical component of lipopolysaccharide involved in stimulating activation of TLRs is the lipid A subunit, which is composed almost entirely of long-chain fatty acids. The specific fatty acid composition (triacyl or diacyl) appears to determine which receptor (TLR-2 or -4) is activated (15). The activation of these receptors on cells of the innate immune system leads to the production of cytokines, chemokines, and the up-regulation of cell surface molecules.…”

mentioning

confidence: 99%

Toll-like Receptor-2 Is Essential for the Development of Palmitate-induced Insulin Resistance in Myotubes

Senn

2006

Journal of Biological Chemistry

234

191

View full text Add to dashboard Cite

Fatty acids can activate proinflammatory pathways leading to the development of insulin resistance, but the mechanism is undiscovered. Toll like receptor 2 (TLR2) recognizes lipids, activates proinflammatory pathways, and is genetically associated with inflammatory diseases. This study aimed to examine the role of TLR2 in palmitate-induced insulin resistance in C2C12 myotubes. Treatment with palmitate rapidly induced the association of myeloid differentiation factor 88 (MyD88) with the TLR2 receptor, activated the stress-linked kinases p38, JNK, and protein kinase C, induced degradation of IB␣, and increased NF-B DNA binding. The activation of these pathways by palmitate was sensitive and temporally regulated and occurred within the upper physiologic range of saturated fatty acid concentrations in vivo, suggesting a receptor-mediated event and not simple lipotoxicity. When compared with an equimolar concentration of palmitate, fibroblast-stimulating lipopeptide-1, a known TLR2 ligand, was a slightly more potent activator of signal transduction and interleukin (IL)-6 production. Palmitate inhibited insulin signal transduction in C2C12 cells beginning 1-2 h after exposure and reached a maximum at 12-16 h. An antagonist TLR2 antibody, mAb 2.5, led to a 50 -60% decrease in palmitate-induced IL-6 production and partially restored insulin signal transduction, whereas an isotype-matched control antibody had no effect. RNA interference-mediated inhibition of TLR2 and MyD88 expression in C2C12 muscle cells resulted in a near complete inhibition of palmitate-induced insulin resistance and IL-6 production. This study provides strong evidence that TLR2 mediates the initial events of fatty acid-induced insulin resistance in muscle.

show abstract

“…In addition to their roles in pathogenesis, bacterial lipoproteins can activate microbicidal activities of monocytes and macrophages through Toll-like receptor 2 (TLR2) (6,27,34,49). Since E. chaffeensis infection leads to the downregulation of TLR2 in the host cells in vitro (30), it is expected that E. chaffeensis lipoproteins cannot induce effective antimicrobicidal activity in already infected monocytes and macrophages.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis of and Immune Responses toEhrlichia chaffeensisLipoproteins

et al. 2008

View full text Add to dashboard Cite

Ehrlichia chaffeensis is an obligately intracellular gram-negative bacterium and is the etiologic agent of human monocytic ehrlichiosis (HME). Although E. chaffeensis induces the generation of several cytokines and chemokines by leukocytes, E. chaffeensis lacks lipopolysaccharide and peptidoglycan. Bioinfomatic analysis of the E. chaffeensis genome, however, predicted genes encoding 15 lipoproteins and 3 posttranslational lipoprotein-processing enzymes. The present study showed that by use of multidimensional liquid chromatography followed by tandem mass spectrometry, all predicted lipoproteins as well as lipoprotein-processing enzymes were expressed by E. chaffeensis cultured in the human promyelocytic leukemia cell line HL-60. Consistent with this observation, a signal peptidase II inhibitor, globomycin, was found to inhibit E. chaffeensis infection and lipoprotein processing in HL-60 cell culture. To study in vivo E. chaffeensis lipoprotein expression and host immune responses to E. chaffeensis lipoproteins, 13 E. chaffeensis lipoprotein genes were cloned into a mammalian expression vector. When the DNA constructs were inoculated into naïve dogs, or when dogs were infected with E. chaffeensis, the animals developed delayed-type hypersensitivity reactions at cutaneous sites of the DNA construct deposition and serum antibodies to these lipoproteins. This is the first demonstration of lipoprotein expression and elicitation of immune responses by a member of the order Rickettsiales. Multiple lipoproteins expressed by E. chaffeensis in vitro and in vivo may play key roles in pathogenesis and immune responses in HME.

show abstract

Triacyl-lipopentapeptide adjuvants: TLR2-dependent activation of macrophages and modulation of receptor-mediated cell activation by altering acyl-moieties

Cited by 19 publications

References 55 publications

MyD88-Dependent Signaling Contributes to Protection following Bacillus anthracis Spore Challenge of Mice: Implications for Toll-Like Receptor Signaling

MyD88-Dependent Signaling Contributes to Protection following Bacillus anthracis Spore Challenge of Mice: Implications for Toll-Like Receptor Signaling

Toll-like Receptor-2 Is Essential for the Development of Palmitate-induced Insulin Resistance in Myotubes

Proteomic Analysis of and Immune Responses toEhrlichia chaffeensisLipoproteins

Contact Info

Product

Resources

About