Lysophosphatidic acid inhibits bacterial endotoxin-induced pro-inflammatory response: Potential anti-inflammatory signaling pathways

Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina, USA.
Molecular Medicine (Impact Factor: 4.51). 11/2007; 14(7-8):422-8. DOI: 10.2119/2007-00106.Fan
Source: PubMed


Previous studies have demonstrated that heterotrimeric guanine nucleotide-binding regulatory (Gi) protein-deficient mice exhibit augmented inflammatory responses to lipopolysaccharide (LPS). These findings suggest that Gi protein agonists will suppress LPS-induced inflammatory gene expression. Lysophosphatidic acid (LPA) activates G protein-coupled receptors leading to Gi protein activation. We hypothesized that LPA will inhibit LPS-induced inflammatory responses through activation of Gi-coupled anti-inflammatory signaling pathways. We examined the anti-inflammatory effect of LPA on LPS responses both in vivoand in vitro in CD-1 mice. The mice were injected intravenously with LPA (10 mg/kg) followed by intraperitoneal injection of LPS (75 mg/kg for survival and 25 mg/kg for other studies). LPA significantly increased the mice survival to endotoxemia (P < 0.05). LPA injection reduced LPS-induced plasma TNF-α production (69 ± 6%, P < 0.05) and myeloperoxidase (MPO) activity in lung (33 ± 9%, P < 0.05) as compared to vehicle injection. LPS-induced plasma IL-6 was unchanged by LPA. In vitro studies with peritoneal macrophages paralleled results from in vivostudies. LPA (1 and 10 μM) significantly inhibited LPS-induced TNFα production (61 ± 9% and 72 ± 9%, respectively, P < 0.05) but not IL-6. We further demonstrated that the anti-inflammatory effect of LPA was reversed by ERK 1/2 and phosphatase inhibitors, suggesting that ERK 1/2 pathway and serine/threonine phosphatases are involved. Inhibition of phosphatidylinositol 3 (PI3) kinase signaling pathways also partially reversed the LPA anti-inflammatory response. However, LPA did not alter NFκB and peroxisome proliferator-activated receptor γ (PPARγ) activation. Inhibitors of PPARγ did not alter LPA-induced inhibition of LPS signaling. These studies demonstrate that LPA has significant anti-inflammatory activities involving activation of ERK 1/2, serine/threonine phosphatases, and PI3 kinase signaling pathways.

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    • "Based on the literature, we first assessed the LPA dose response with 10–40-mg/kg doses to test if mice could tolerate four intraperitoneal (i.p.) injections by monitoring body weight and assessing fur appearance (Fan et al. 2008). Only the 40-mg/kg dose resulted in loss of body weight after four injections; hence the 30-mg/kg dose was used for further study. "
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    ABSTRACT: Our previous work has suggested that traumatic noise activates Rho-GTPase pathways in cochlear outer hair cells (OHCs), resulting in cell death and noise-induced hearing loss (NIHL). In this study, we investigated Rho effectors, Rho-associated kinases (ROCKs), and the targets of ROCKs, the ezrin-radixin-moesin (ERM) proteins, in the regulation of the cochlear actin cytoskeleton using adult CBA/J mice under conditions of noise-induced temporary threshold shift (TTS) and permanent threshold shift (PTS) hearing loss, which result in changes to the F/G-actin ratio. The levels of cochlear ROCK2 and p-ERM decreased 1 h after either TTS- or PTS-noise exposure. In contrast, ROCK2 and p-ERM in OHCs decreased only after PTS-, not after TTS-noise exposure. Treatment with lysophosphatidic acid, an activator of the Rho pathway, resulted in significant reversal of the F/G-actin ratio changes caused by noise exposure and attenuated OHC death and NIHL. Conversely, the down-regulation of ROCK2 by pretreatment with ROCK2 siRNA reduced the expression of ROCK2 and p-ERM in OHCs, exacerbated TTS to PTS, and worsened OHC loss. Additionally, pretreatment with siRNA against radixin, an ERM protein, aggravated TTS to PTS. Our results indicate that a ROCK2-mediated ERM-phosphorylation signaling cascade modulates noise-induced hair cell loss and NIHL by targeting the cytoskeleton. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text · Article · Feb 2015 · Journal of Neurochemistry
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    • "Further, LPA enhanced cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) release in HBEpCs [23] suggesting a protective role in the innate immunity response and tissue repair process in airway inflammation [24,25]. Recently, Fan et al. showed that intravenous injection with LPA attenuated bacterial endotoxin-induced plasma TNF-α production and myeloperoxidase activity in mouse lung, suggesting an anti-inflammatory role of LPA in a murine model of acute lung injury [26]. In addition to its anti-inflammatory effect, LPA regulated E-cadherin intracellular trafficking and airway epithelial barrier integrity and intratracheal post-treatment with LPA reduced neutrophil influx, protein leak, and E-cadherin shedding in bronchoalveolar lavage (BAL) fluids in a murine model of LPS-induced acute lung injury [27]. "
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    ABSTRACT: Lysophosphatidic acid (LPA) plays a critical role in airway inflammation through G protein-coupled LPA receptors (LPA1-3). We have demonstrated that LPA induced cytokine and lipid mediator release in human bronchial epithelial cells. Here we provide evidence for the role of LPA and LPA receptors in Th2-dominant airway inflammation. Wild type, LPA1 heterozygous knockout mice (LPA1+/-), and LPA2 heterozygous knockout mice (LPA2+/-) were sensitized with inactivated Schistosoma mansoni eggs and local antigenic challenge with Schistosoma mansoni soluble egg Ag (SEA) in the lungs. Bronchoalveolar larvage (BAL) fluids and lung tissues were collected for analysis of inflammatory responses. Further, tracheal epithelial cells were isolated and challenged with LPA. BAL fluids from Schistosoma mansoni egg-sensitized and challenged wild type mice (4 days of challenge) showed increase of LPA level (approximately 2.8 fold), compared to control mice. LPA2+/- mice, but not LPA1+/- mice, exposed to Schistosoma mansoni egg revealed significantly reduced cell numbers and eosinophils in BAL fluids, compared to challenged wild type mice. Both LPA2+/- and LPA1+/- mice showed decreases in bronchial goblet cells. LPA2+/- mice, but not LPA1+/- mice showed the decreases in prostaglandin E2 (PGE2) and LPA levels in BAL fluids after SEA challenge. The PGE2 production by LPA was reduced in isolated tracheal epithelial cells from LPA2+/- mice. These results suggest that LPA and LPA receptors are involved in Schistosoma mansoni egg-mediated inflammation and further studies are proposed to understand the role of LPA and LPA receptors in the inflammatory process.
    Full-text · Article · Nov 2009 · Respiratory research
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