Toll-like receptor (TLR) 2–9 agonists-induced cytokines and chemokines: I. Comparison with T cell receptor-induced responses

Ghosh, Tarun Kanti; Mickelson, Dan J.; Fink, Jason; Solberg, Jonathan; Inglefield, Jon R.; Hook, Derek J.; Gupta, Shalley K.; Gibson, Sheila J.; Alkan, Şefik Ş.

doi:10.1016/j.cellimm.2006.12.002

Cited by 104 publications

(95 citation statements)

References 55 publications

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“…It is also possible that macrophages from RA ST, like those from RA synovial fluid, have higher TLR5 expression compared with RA monocytes, and maybe the presence of proinflammatory factors is required to enhance TLR5 expression during the differentiation process, which is available in the RA joint and unavailable in the culture system. In contrast to our results, other studies were unable to detect TNF-a production when normal monocytes were activated with flagellin (50). This may be due to lower levels of TLR5 expression in normal cells compared with RA monocytes as well as isolation and culturing methods.…”

Section: Discussioncontrasting

confidence: 99%

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The Role of IL-17 in the Angiogenesis of Rheumatoid Arthritis

Shahrara¹,

Kim²,

Chen³

2013

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Section: Discussioncontrasting

confidence: 99%

“…This may be due to lower levels of TLR5 expression in normal cells compared with RA monocytes as well as isolation and culturing methods. However, consistent with our data, they were able to demonstrate high levels of CCL2 following TLR5 ligation in normal monocytes (50).…”

Section: Discussionsupporting

confidence: 91%

The Role of IL-17 in the Angiogenesis of Rheumatoid Arthritis

Shahrara¹,

Kim²,

Chen³

2013

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“…In addition, TLR ligands function as costimulatory factors to induce T-cell activation (36,37). In this study, we determined whether stimulation of TLR2, 4, 5 and 7, with specific TLR agonists, can modulate the suppression of T-cell responses after EtOH intoxication and burn injury.…”

Section: Discussionmentioning

confidence: 99%

Activation of Toll-Like Receptor 2 Prevents Suppression of T-Cell Interferon γ Production by Modulating p38/Extracellular Signal-Regulated Kinase Pathways following Alcohol and Burn Injury

Rendón

Akhtar

et al. 2012

Mol Med

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Recent studies indicate that toll-like receptors (TLRs) are expressed on T cells and that these receptors directly or indirectly activate the adaptive immune system. We have shown previously that acute alcohol/ethanol (EtOH) intoxication combined with burn injury suppresses mesenteric lymph node (MLN) T-cell interleukin-2 (IL-2) and interferon γ (IFN-γ) production. We examined whether direct stimulation of T cells with TLR2, 4, 5 and 7 agonists modulates CD3-mediated T-cell IL-2/IFN-γ release following EtOH and burn injury. Male mice were gavaged with EtOH (2.9 gm/kg) 4 h prior to receiving an ~12.5% total body surface area sham or full-thickness burn injury. Animals were killed on d 1 after injury and T cells were purified from MLN and spleens. T cells were cultured with plate-bound anti-CD3 in the presence or absence of various TLR ligands. Although TLR2, 4 and 5 agonists potentiate anti-CD3-dependent IFN-γ by T cells, the TLR2 agonist alone induced IFN-γ production independent of CD3 stimulation. Furthermore, T cells were treated with inhibitors of myeloid differentiation primary response protein 88 (MyD88), TIR domain-containing adaptor protein (TIRAP), p38 and/or extracellular signal-regulated kinase (ERK) to determine the mechanism by which TLR2 mediates IL-2/IFN-γ production. IL-2 was not influenced by TLR agonists. MyD88 and TIRAP inhibitory peptides dose-dependently diminished the ability of T cells to release IFN-γ. p38 and ERK inhibitors also abolished TLR2-mediated T-cell IFN-γ. Together, our findings suggest that TLR2 directly modulates T-cell IFN-γ production following EtOH and burn injury, independent of antigen-presenting cells. Furthermore, we demonstrated that MyD88/TIRAP-dependent p38/ERK activation is critical to TLR2-mediated T-cell IFN-γ release following EtOH and burn injury.

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“…This is in clear distinction to the expression of human TLR7 and TLR9 in the endosome of plasmacytoid dendritic cells-a population of DC with a very different phenotype and biology compared with mDC (12,13). Thus, activation of TLR8 is expected to stimulate the release of distinct inflammatory mediators, including Th1-polarizing cytokines, chemokines, and other acute phase proteins (5,11,(14)(15)(16) compared with TLR9 agonists that have previously been evaluated in patients with cancer (17). Because the structure of TLR8 is highly conserved among primates (16), the cynomolgus monkey was considered a relevant species for the preliminary pharmacologic assessments of VTX-2337.…”

Section: Introductionmentioning

confidence: 99%

“…The effects of activating the innate response include alterations in normal leukocyte circulation through blood and tissues, release of soluble mediators, upregulation of antigen processing and presentation to helper (CD4) and cytolytic (CD8) T cells, and increases in NK cell function. In the context of an existing cancer, these effects should act in concert to increase the innate and adaptive immune responses to tumor cells, and TLR agonists may be potential candidates for the treatment of various malignancies in humans (1)(2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

A Phase I Dose-Finding Study of the Novel Toll-like Receptor 8 Agonist VTX-2337 in Adult Subjects with Advanced Solid Tumors or Lymphoma

Northfelt¹,

Ramanathan

Cohen³

et al. 2014

Clinical Cancer Research

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Purpose: This phase I, open-label, uncontrolled, ascending-dose study explored the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacology of the TLR8 agonist VTX-2337 in subjects with advanced solid tumors or lymphoma.Experimental Design: VTX-2337 doses (0.1-3.9 mg/m 2 ) were administered subcutaneously on days 1, 8, and 15 of each 28-day cycle. Safety/tolerability assessments included adverse events (AE); physical, ophthalmologic, and laboratory evaluations; and electrocardiograms. Dose-limiting toxicities (DLT) were evaluated during the first cycle. Pharmacokinetics were evaluated after the first dose. Plasma samples were quantitatively assessed for chemokines, cytokines, and other inflammatory mediators. Antitumor activity was assessed.Results: Thirty-three subjects were enrolled in 8 cohorts and received an average of 2 treatment cycles (range, 1-8 cycles). Most AEs were grades 1 to 2; the most common drug-related AEs were injection site reactions, chills, pyrexia, and influenza-like illness. One DLT was reported: grade 3 hypotension (3.9 mg/m 2

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Toll-like receptor (TLR) 2–9 agonists-induced cytokines and chemokines: I. Comparison with T cell receptor-induced responses

Cited by 104 publications

References 55 publications

The Role of IL-17 in the Angiogenesis of Rheumatoid Arthritis

The Role of IL-17 in the Angiogenesis of Rheumatoid Arthritis

Activation of Toll-Like Receptor 2 Prevents Suppression of T-Cell Interferon γ Production by Modulating p38/Extracellular Signal-Regulated Kinase Pathways following Alcohol and Burn Injury

A Phase I Dose-Finding Study of the Novel Toll-like Receptor 8 Agonist VTX-2337 in Adult Subjects with Advanced Solid Tumors or Lymphoma

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