Phospholipase Cɛ has a crucial role in ultraviolet B-induced neutrophil-associated skin inflammation by regulating the expression of CXCL1/KC

Oka, Masahiro; Edamatsu, Hironori; Kunisada, Makoto; Hu, Lizhi; Takenaka, Nobuyuki; Sakaguchi, Masanobu; Kataoka, Tohru; Nishigori, Chikako

doi:10.1038/labinvest.2011.10

Cited by 24 publications

(20 citation statements)

References 46 publications

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“…PLCε knockout mice exhibit increased susceptibility to hypertrophy and cardiac enlargement in response to adrenergic stress [92]. PLCε knockout mice have also been shown to have diminished generation of proinflammatory mediators in models of cancer, in particular skin cancer [93, 94]. …”

Section: Activation Of Phospholipases By Rhoamentioning

confidence: 99%

Lysophospholipid receptor activation of RhoA and lipid signaling pathways

Xiang¹,

Dusaban²,

Brown³

2013

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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The lysophospholipids sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) signal through G-protein coupled receptors (GPCRs) which couple to multiple G-proteins and their effectors. These GPCRs are quite efficacious in coupling to the Gα12/13 family of G-proteins, which stimulate guanine nucleotide exchange factors (GEFs) for RhoA. Activated RhoA subsequently regulates downstream enzymes that transduce signals which affect the actin cytoskeleton, gene expression, cell proliferation and cell survival. Remarkably many of the enzymes regulated downstream of RhoA either use phospholipids as substrates (e.g. phospholipase D, phospholipase C-epsilon, PTEN, PI3 kinase) or are regulated by phospholipid products (e.g. protein kinase D, Akt). Thus lysophospholipids signal from outside of the cell and control phospholipid signaling processes within the cell that they target. Here we review evidence suggesting an integrative role for RhoA in responding to lysophospholipids upregulated in the pathophysiological environment, and in transducing this signal to cellular responses through effects on phospholipid regulatory or phospholipid regulated enzymes.

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Section: Activation Of Phospholipases By Rhoamentioning

confidence: 99%

Lysophospholipid receptor activation of RhoA and lipid signaling pathways

Xiang¹,

Dusaban²,

Brown³

2013

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…In addition, there is a role for PLCe in GPCR-mediated hypertrophic growth of cardiomyocytes (31,32). PLCe has also been implicated in the induction of the inflammatory mediators TGF-β and cyclooxygenase 2 (COX-2) in response to chemical carcinogens or UV irradiation (33)(34)(35)(36). There is, however, no available information on whether GPCRs use PLCe signaling to regulate inflammatory gene expression.…”

mentioning

confidence: 99%

Phospholipase Cɛ links G protein-coupled receptor activation to inflammatory astrocytic responses

Dusaban

Purcell²,

Rockenstein³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Neuroinflammation underlies many diseases of the central nervous system (CNS) and the role of astrocytes in this process is increasingly recognized. Thrombin and the lysophospholipids, LPA and S1P are generated during injury and can activate G‐protein coupled receptors (GPCRs) on astrocytes. We hypothesized that GPCRs that couple to RhoA induce inflammatory gene expression in astrocytes through phospholipase C‐epsilon (PLCε). Using wild‐type (WT) and PLCε (KO) astrocytes, we recently demonstrated that thrombin, LPA, and S1P signal through PLCε to mediate sustained PKD activation and subsequently activation of NFκB to induce expression of inflammatory genes including COX‐2, IL‐1β, and IL‐6 (Dusaban, SS et al. PNAS, 2013). We are currently investigating the molecular mechanism by which PLCε mediates sustained PKD activation and downstream inflammatory responses. Preliminary data using Golgi targeted PKD FRET reporters suggests that PLCε mediates sustained activation of PKD at the Golgi. We also find that disrupting the Golgi with brefeldin A inhibits both PKD activation and COX‐2 expression. We further determined that COX‐2 gene expression was induced through PLCε following in vitro wounding and in vivo cortical stab wound injury. In light of growing evidence for a role of glial cells and S1P receptors in neuroinflammation, we investigated the S1P receptor subtypes coupled to PLCε and its downstream targets. Taking advantage of receptor KO astrocytes and receptor knockdown, we determined that coupling occurs primarily through the S1P3 receptor. Future work is aimed at identifying other GPCRs that signal through PLCε to mediate neuroinflammatory responses. Grant Funding Source: GM 36927

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“…PLCε positively regulated proliferation of dermal fibroblasts (9), a major source of matrix protein production. In the skin, PLCε stimulated proinflammatory mediator production, including keratinocyte‐derived chemokine (KC), the murine functional homologue of interleukin (IL)‐8 (11), IL‐1β, and tumor necrosis factor (TNF)‐α (12). The PLCε‐mediated increase in KC was accompanied by neutrophilia (11).…”

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confidence: 99%

Epac1 and Epac2 are differentially involved in inflammatory and remodeling processes induced by cigarette smoke

et al. 2014

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Cigarette smoke (CS) induces inflammatory responses characterized by increase of immune cells and cytokine release. Remodeling processes, such as mucus hypersecretion and extracellular matrix protein production, are also directly or indirectly induced by CS. Recently, we showed that activation of the exchange protein directly activated by cAMP (Epac) attenuates CS extract-induced interleukin (IL)-8 release from cultured airway smooth muscle cells. Using an acute, short-term model of CS exposure, we now studied the role of Epac1, Epac2, and the Epac effector phospholipase-Cε (PLCε) in airway inflammation and remodeling in vivo. Compared to wild-type mice exposed to CS, the number of total inflammatory cells, macrophages, and neutrophils and total IL-6 release was lower in Epac2(-/-) mice, which was also the case for neutrophils and IL-6 in PLCε(-/-) mice. Taken together, Epac2, acting partly via PLCε, but not Epac1, enhances CS-induced airway inflammation in vivo. In total lung homogenates of Epac1(-/-) mice, MUC5AC and matrix remodeling parameters (transforming growth factor-β1, collagen I, and fibronectin) were increased at baseline. Our findings suggest that Epac1 primarily is capable of inhibiting remodeling processes, whereas Epac2 primarily increases inflammatory processes in vivo.

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Phospholipase Cɛ has a crucial role in ultraviolet B-induced neutrophil-associated skin inflammation by regulating the expression of CXCL1/KC

Cited by 24 publications

References 46 publications

Lysophospholipid receptor activation of RhoA and lipid signaling pathways

Lysophospholipid receptor activation of RhoA and lipid signaling pathways

Phospholipase Cɛ links G protein-coupled receptor activation to inflammatory astrocytic responses

Epac1 and Epac2 are differentially involved in inflammatory and remodeling processes induced by cigarette smoke

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