Lysophosphatidic acid induces expression of genes in human oral keratinocytes involved in wound healing

Thorlakson, Hong H.; Engen, Stian André; Schreurs, Olav; Schenck, Karl; Blix, Inger J. Schytte

doi:10.1016/j.archoralbio.2017.04.008

Cited by 8 publications

(6 citation statements)

References 57 publications

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“…Thrombin treatment activated JNK, while curcumin inhibited CCN2 expression through JNK suppression. CCN2 is also induced by lysophosphatidic acid (LPA), in oral epithelial cells and gingival fibroblasts [128,129] and this effect can be significantly inhibited by TGFβ type I receptor/ALK5, Smad3, and JNK inhibitors but not ERK, P38, and MAPK inhibitors [129,130]. It has been proposed that LPA produced due to surgical wounds could contribute to the recurrence of gingival overgrowth by upregulating CCN2 expression in HGFs, an effect that is mediated by Smad3 and JNK activation and ALK5 transactivation [130], further highlighting the role of JNK in regulating cellular responses in gingival overgrowth.…”

Section: Gingival Fibroblasts and Jnkmentioning

confidence: 99%

JNK Signaling as a Key Modulator of Soft Connective Tissue Physiology, Pathology, and Healing

Nikoloudaki

Brooks

Peidl

et al. 2020

IJMS

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In healthy individuals, the healing of soft tissues such as skin after pathological insult or post injury follows a relatively predictable and defined series of cell and molecular processes to restore tissue architecture and function(s). Healing progresses through the phases of hemostasis, inflammation, proliferation, remodeling, and concomitant with re-epithelialization restores barrier function. Soft tissue healing is achieved through the spatiotemporal interplay of multiple different cell types including neutrophils, monocytes/macrophages, fibroblasts, endothelial cells/pericytes, and keratinocytes. Expressed in most cell types, c-Jun N-terminal kinases (JNK) are signaling molecules associated with the regulation of several cellular processes involved in soft tissue wound healing and in response to cellular stress. A member of the mitogen-activated protein kinase family (MAPK), JNKs have been implicated in the regulation of inflammatory cell phenotype, as well as fibroblast, stem/progenitor cell, and epithelial cell biology. In this review, we discuss our understanding of JNKs in the regulation of cell behaviors related to tissue injury, pathology, and wound healing of soft tissues. Using models as diverse as Drosophila, mice, rats, as well as human tissues, research is now defining important, but sometimes conflicting roles for JNKs in the regulation of multiple molecular processes in multiple different cell types central to wound healing processes. In this review, we focus specifically on the role of JNKs in the regulation of cell behavior in the healing of skin, cornea, tendon, gingiva, and dental pulp tissues. We conclude that while parallels can be drawn between some JNK activities and the control of cell behavior in healing, the roles of JNK can also be very specific modes of action depending on the tissue and the phase of healing.

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Section: Gingival Fibroblasts and Jnkmentioning

confidence: 99%

JNK Signaling as a Key Modulator of Soft Connective Tissue Physiology, Pathology, and Healing

Nikoloudaki

Brooks

Peidl

et al. 2020

IJMS

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“…Several stimuli, such as glomerular injury, can induce IL-6 production from renal TECs, thus promoting a TEC-glomeruli crosstalk [53]. LPA has been shown before to induce IL-6 production in human bronchial epithelial cells [55], keratinocytes [56], and mesangial cells [38]. Exposure of mesangial cells to IL-6 and its soluble receptor (sIL-6R) together promotes the synthesis and secretion of CCL2/MCP1 and subsequently enhances monocyte recruitment [57].…”

Section: Discussionmentioning

confidence: 99%

“…IL-8, which is the molecule most prominently induced by LPA at the mRNA level, is a key mediator associated with inflammation as it causes the activation and chemotaxis of neutrophils, leading them towards the site of inflammation [60]. LPA has been shown to induce IL-8 production before, in the bronchial epithelial cells of the lungs [55,61,62], keratinocytes [56], and epithelial ovarian cancer cells [46]. In the kidney, human renal cortical epithelial cells express IL-8 upon incubation with IL-1β, TNF, or LPS [63].…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidic Acid Is a Proinflammatory Stimulus of Renal Tubular Epithelial Cells

Magkrioti

Antonopoulou

Fanidis

et al. 2022

IJMS

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Chronic kidney disease (CKD) refers to a spectrum of diseases defined by renal fibrosis, permanent alterations in kidney structure, and low glomerular-filtration rate. Prolonged epithelial-tubular damage involves a series of changes that eventually lead to CKD, highlighting the importance of tubular epithelial cells in this process. Lysophosphatidic acid (LPA) is a bioactive lipid that signals mainly through its six cognate LPA receptors and is implicated in several chronic inflammatory pathological conditions. In this report, we have stimulated human proximal tubular epithelial cells (HKC-8) with LPA and 175 other possibly pathological stimuli, and simultaneously detected the levels of 27 intracellular phosphoproteins and 32 extracellular secreted molecules with multiplex ELISA. This quantification revealed a large amount of information concerning the signaling and the physiology of HKC-8 cells that can be extrapolated to other proximal tubular epithelial cells. LPA responses clustered with pro-inflammatory stimuli such as TNF and IL-1, promoting the phosphorylation of important inflammatory signaling hubs, including CREB1, ERK1, JUN, IκΒα, and MEK1, as well as the secretion of inflammatory factors of clinical relevance, including CCL2, CCL3, CXCL10, ICAM1, IL-6, and IL-8, most of them shown for the first time in proximal tubular epithelial cells. The identified LPA-induced signal-transduction pathways, which were pharmacologically validated, and the secretion of the inflammatory factors offer novel insights into the possible role of LPA in CKD pathogenesis.

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“…LPA, a member of the lysophospholipid family of bioactive lipids, is known to bind to at least six G-protein coupled receptors (LPAR1-6) 30 and mediate diverse biological actions such as tissue repair and angiogenesis. 31,32 Keratinocytes express several LPA receptors such as lysophosphatidic acid receptor 1 (LPAR1) and LPAR5, 16,33 and LPA induces keratinocyte differentiation through the LPAR1/LPAR5 receptors. 16 RNA-Seq analysis revealed that the expression of LPAR1 but not LPAR5 was increased in Kprp +/− mice (Figure 1B).…”

Section: Increased Expression Of Lpar1 In Kprp Heterozygous Micementioning

confidence: 99%

Keratinocyte proline‐rich protein modulates immune and epidermal response in imiquimod‐induced psoriatic skin inflammation

Matsuno,

Sumida,

Nakanishi

et al. 2023

Experimental Dermatology

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Psoriasis is a persistent inflammatory skin disease thought to arise as a result of the infiltration of inflammatory cells and activation of keratinocytes. Recent advances in basic research and clinical experience revealed that the interleukin (IL)‐23/IL‐17 axis has been identified as a major immune pathway in psoriasis. However, it remains unclear how keratinocyte factors contribute to the pathology of psoriasis. Keratinocyte proline‐rich protein (KPRP) is a proline‐rich insoluble protein, which is present in the epidermis and is likely to be involved in the skin barrier function. Here, to investigate the potential roles of KPRP in psoriatic skin inflammation, Kprp‐modified mice were applied in the imiquimod (IMQ)‐induced skin inflammation model, which develops psoriasis‐like epidermal hyperplasia and cutaneous inflammation features. Then, heterozygous knockout (Kprp+/−) but not homozygous knockout (Kprp−/−) mice displayed attenuated skin erythema compared to control wild‐type mice. In addition, RNA sequencing, quantitative PCR and/or histological analysis detected changes in the expression of several molecules related to psoriatic inflammation or keratinocyte differentiation in Kprp+/− mice, but not Kprp−/− mice. Further analysis exhibited reduced IL‐17‐producing γδlow T cells and amplified epidermal hyperplasia in Kprp+/− mice, which were implied to be related to decreased expression of β‐defensins and increased expression of LPAR1 (Lysophosphatidic acid receptor 1), respectively. Thus, our results imply that KPRP has the potential as a therapeutic target in psoriatic skin inflammation.

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Lysophosphatidic acid induces expression of genes in human oral keratinocytes involved in wound healing

Cited by 8 publications

References 57 publications

JNK Signaling as a Key Modulator of Soft Connective Tissue Physiology, Pathology, and Healing

JNK Signaling as a Key Modulator of Soft Connective Tissue Physiology, Pathology, and Healing

Lysophosphatidic Acid Is a Proinflammatory Stimulus of Renal Tubular Epithelial Cells

Keratinocyte proline‐rich protein modulates immune and epidermal response in imiquimod‐induced psoriatic skin inflammation

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