Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Macrophages can be activated through TLRs for a variety of innate immune responses. In contrast with the wealth of data existing on TLR-dependent gene expression and resultant cytokine production, very little is known on the mechanisms governing TLR-mediated arachidonic acid (AA) mobilization and subsequent eicosanoid production. We have previously reported the involvement of both cytosolic group IVA phospholipase A(2) (cPLA(2)) and secreted group V phospholipase A(2) (sPLA(2)-V) in regulating the AA mobilization response of macrophages exposed to bacterial LPS, a TLR4 agonist. In the present study, we have used multiple TLR agonists to define the role of various PLA(2)s in macrophage AA release via TLRs. Activation of P388D(1) and RAW2647.1 macrophage-like cells via TLR1/2, TLR2, TLR3, TLR4, TLR6/2, and TLR7, but not TLR5 or TLR9, resulted in AA mobilization that appears to involve the activation of both cPLA(2) and sPLA(2) but not of calcium-independent phospholipase A(2). Furthermore, inhibition of sPLA(2)-V by RNA interference or by two cell-permeable compounds, namely scalaradial and manoalide, resulted in a marked reduction of the phosphorylation of ERK1/2 and cPLA(2) via TLR1/2, TLR2, TLR3, and TLR4, leading to attenuated AA mobilization. Collectively, the results suggest a model whereby sPLA(2)-V contributes to the macrophage AA mobilization response via various TLRs by amplifying cPLA(2) activation through the ERK1/2 phosphorylation cascade.
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PMID:Coordinate regulation of TLR-mediated arachidonic acid mobilization in macrophages by group IVA and group V phospholipase A2s. 1926 67

Small-molecule agonists for the Toll-like receptors (TLR) 7 and 8 are effective for the immunotherapy of skin cancer when used as topical agents. Their systemic use has however been largely unsuccessful due to dose-limiting toxicity. We propose a polymer-based nanodelivery system to target resiquimod, a TLR7 ligand, to the lymph node in order to focus the immunostimulatory activity and to prevent a generalized inflammatory response. We demonstrate successful encapsulation of resiquimod in methoxypoly(ethylene glycol)-b-poly(DL-lactic acid) (mPEG-PLA) and mixed poly(DL-lactic-co-glycolic acid) (PLGA)/mPEG-PLA nanoparticles. We show that these particles are taken up mainly by dendritic cells and macrophages, which are the prime initiators of anticancer immune responses. Nanoparticles loaded with resiquimod activate these cells, demonstrating the availability of the immune-stimulating cargo. The unloaded particles are non-inflammatory and do not have cytotoxic activity on immune cells. Following subcutaneous injection in mice, mPEG-PLA and PLGA/mPEG-PLA nanoparticles are detected in dendritic cells and macrophages in the draining lymph nodes, demonstrating the targeting potential of these particles. Thus, polymer-based nanoparticles represent a promising delivery system that allows lymph node targeting for small-molecule TLR7 agonists in the context of systemic cancer immunotherapy.
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PMID:Polymer-based nanoparticles loaded with a TLR7 ligand to target the lymph node for immunostimulation. 2915 65

Cancer immunotherapy can be augmented with toll-like receptor agonist (TLRa) adjuvants, which interact with immune cells to elicit potent immune activation. Despite their potential, use of many TLRa compounds has been limited clinically due to their extreme potency and lack of pharmacokinetic control, causing systemic toxicity from unregulated systemic cytokine release. Herein, we overcome these shortcomings by generating poly(ethylene glycol)-poly(lactic acid) (PEG-PLA) nanoparticles (NPs) presenting potent TLR7/8a moieties on their surface. The NP platform allows precise control of TLR7/8a valency and resulting surface presentation through self-assembly using nanoprecipitation. We hypothesize that the pharmacokinetic profile of the NPs minimizes systemic toxicity, localizing TLR7/8a presentation to the tumor bed and tumor-draining lymph nodes. In conjunction with antiprogrammed death-ligand 1 (anti-PD-L1) checkpoint blockade, peritumoral injection of TLR7/8a NPs slows tumor growth, extends survival, and decreases systemic toxicity in comparison to the free TLR7/8a in a murine colon adenocarcinoma model. These NPs constitute a modular platform for controlling pharmacokinetics of immunostimulatory molecules, resulting in increased potency and decreased toxicity.
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PMID:Nanoparticles Presenting Potent TLR7/8 Agonists Enhance Anti-PD-L1 Immunotherapy in Cancer Treatment. 3281 60