E5564 (Eritoran) inhibits lipopolysaccharide-induced cytokine production in human blood monocytes

Czeslick, Elke; Struppert, A; Simm, Andreas; Sablotzki, Armin

doi:10.1007/s00011-006-6057-3

Cited by 51 publications

(37 citation statements)

References 12 publications

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“…49 In the past, TLR4 in "effector cells" such as macrophages were considered the main target of these drugs. 50 However, as "conduit cells" for immune cell transport, the active contribution of LECs in LPS-induced inflammation in our study implies that the control and modulation of TLR4 function in LECs can be a potential and novel alternative target to overcome Gram-negative bacteria-induced mortality.…”

Section: Discussionmentioning

confidence: 76%

Toll-like receptor 4 in lymphatic endothelial cells contributes to LPS-induced lymphangiogenesis by chemotactic recruitment of macrophages

Kang

Lee

Kim

et al. 2009

Blood

111

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The lymphatic vessel is a major conduit for immune cell transport; however, little is known about how lymphatic vessels regulate immune cell trafficking and how lymphatic vessels themselves respond to inflammation. Toll-like receptor 4 (TLR4) plays a central role in lipopolysaccharide (LPS)-induced inflammation, but the role of TLR4 in lymphatic endothelial cells (LECs) is poorly understood. Here, we found that LECs express high amounts of TLR4 in the intracellular region, and that the TLR4 of LECs is the main mediator of nuclear factor-B (NF-B) activation by LPS. LPS-TLR4 signaling in LECs resulted in the production of various chemokines for chemotaxis of macrophage. In addition, TLR4 in LECs actively contributed to the recruitment of macrophages to the draining lymphatic vessel. Furthermore, the macrophages that infiltrated into the lymphatic vessel induced lymphangiogenesis by secreting lymphangiogenic growth factors. These phenomena were largely attenuated not only in the mice defective in TLR4 signaling but also in the chimeric mice defective in TLR4 signaling that were recipients for bone marrow transplantation from normal TLR4-signaling mice. IntroductionToll-like receptor 4 (TLR4) is a pattern recognition receptor (PRR) that initiates the innate immune response against Gram-negative bacteria infection by recognizing lipopolysaccharide (LPS), the prominent component of the bacteria cell wall. 1 The role of TLR4 and its signaling pathway has been extensively studied in macrophages, as these cells abundantly express TLR4 and are crucial players in LPS-induced immune responses. 2,3 In response to infection by Gram-negative bacteria, resident macrophages recognize LPS via surface TLR4, 1 process the pathogen, migrate to the regional draining lymph node (DLN), and present the antigen to T lymphocytes, resulting in induction of the adaptive immune response. [4][5][6] During this process, TLR4 activates nuclear factor-B (NF-B), a canonical transcription factor that mediates various inflammatory responses, which results in the activation of a variety of proinflammatory genes in macrophages. 4,[7][8][9] TLR4 is also expressed in nonimmune cells, including those that constitute the vascular system. 10,11 The lymphatic vessel has a specialized structure distinct from blood vessels in several aspects. Lymphatic endothelial cells (LECs), a major cell type in lymphatic vessels, express specific markers, respond to different growth factors, and constitute blind-ended loose initial lymphatic capillary. [12][13][14][15] Moreover, the function of the lymphatic vessel is unique in that it absorbs macromolecules, transports interstitial fluid, and orchestrates proper trafficking and recirculation of immune cells to the regional lymph node, where the adaptive immune response occurs. 16,17 However, despite the demonstrated function of the lymphatic vessel as a major player in several immune responses, the details on the expression level, signaling pathway, and precise role of TLR4 in LECs remain unknown.De novo lymphangiogene...

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Section: Discussionmentioning

confidence: 76%

Toll-like receptor 4 in lymphatic endothelial cells contributes to LPS-induced lymphangiogenesis by chemotactic recruitment of macrophages

Kang

Lee

Kim

et al. 2009

Blood

111

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“…14,[30][31][32][33] Thus, its analog compounds with a variety of chain-lengths 25-28 were also prepared in order to elucidate the effect of the β-branched acyl chain (Fig. 5A).…”

Section: Resultsmentioning

confidence: 99%

Chemical Hybridization of Vizantin and Lipid A to Generate a Novel LPS Antagonist

Yamamoto

Oda

Kanno

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…AV411 is another TLR-4-targeted antagonist that has potential utility for the treatment of neurological indications (96). In addition to antibodies, a synthetic analog of lipid A eritoran is targeted TLR-4, which inhibited the production of LPS-induced TNF-α and IL-6 (97,98). IMO3100 is a dual TLR-7/TLR-9 antagonist that inhibits TLR ligand-induced gene expression.…”

Section: Current Development In Tlr-targeted Therapeuticsmentioning

confidence: 99%

Cellular crosstalk mechanism of Toll-like receptors in gingival overgrowth (Review)

Subramani

Rathnavelu

Alitheen

2015

International Journal of Molecular Medicine

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Abstract. Gingival overgrowth is an undesirable outcome of systemic medication and is evidenced by the accretion of collagenous components in gingival connective tissues along with diverse degrees of inflammation. Phenytoin therapy has been found to induce the most fibrotic lesions in gingiva, cyclosporine caused the least fibrotic lesions, and nifedipine induced intermediate fibrosis in drug-induced gingival overgrowth. In drug-induced gingival overgrowth, efficient oral hygiene is compromised and has negative consequences for the systemic health of the patients. Toll-like receptors (TLRs) are involved in the effective recognition of microbial agents and play a vital role in innate immunity and inflammatory signaling responses. TLRs stimulate fibrosis and tissue repairs in several settings, although with evident differences between organs. In particular, TLRs exert a distinct effect on fibrosis in organs with greater exposure to TLR ligands, such as the gingiva. Cumulative evidence from diverse sources suggested that TLRs can affect gingival overgrowth in several ways. Numerous studies have demonstrated the expression of TLRs in gingival tissues and suggested its potential role in gingival inflammation, cell proliferation and synthesis of the extracellular matrix which is crucial to the development of gingival overgrowth. In the present review, we assessed the role of TLRs on individual cell populations in gingival tissues that contribute to the progression of gingival inflammation, and the involvement of TLRs in the development of gingival overgrowth. These observations suggest that TLRs provide new insight into the connection among infection, inflammation, drugs and gingival fibrosis, and are therefore efficient therapeutic target molecules. We hypothesize that TLRs are critical for the development and progression of gingival overgrowth, and thus blocking TLR expression may serve as a novel target for antifibrotic therapy.

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E5564 (Eritoran) inhibits lipopolysaccharide-induced cytokine production in human blood monocytes

Abstract: The results of this investigation led us to conclude that E5564 has a remarkable LPS inhibitory activity manifested via down-regulation of the intracellular generation of pro-inflammatory cytokines IL-6 and TNF-alpha in human monocytes.

Cited by 51 publications

References 12 publications

Toll-like receptor 4 in lymphatic endothelial cells contributes to LPS-induced lymphangiogenesis by chemotactic recruitment of macrophages

Toll-like receptor 4 in lymphatic endothelial cells contributes to LPS-induced lymphangiogenesis by chemotactic recruitment of macrophages

Chemical Hybridization of Vizantin and Lipid A to Generate a Novel LPS Antagonist

Cellular crosstalk mechanism of Toll-like receptors in gingival overgrowth (Review)

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