Lysophosphatidic acid induces thrombospondin‐1 production in primary cultured rat cortical astrocytes

Abstract

Lysophosphatidic acid (LPA), a brain membrane‐derived lipid mediator, plays important roles including neural development, function, and behavior. In the present study, the effects of LPA on astrocyte‐derived synaptogenesis factor thrombospondins (TSPs) production were examined by real‐time PCR and western blotting, and the mechanism underlying this event was examined by pharmacological approaches in primary cultured rat cortical astrocytes. Treatment of astrocytes with LPA increased TSP‐1 mRNA, and TSP‐2 mRNA, but not TSP‐4 mRNA expression. TSP‐1 protein expression and release were also increased by LPA. LPA‐induced TSP‐1 production were inhibited by AM966 a LPA1 receptor antagonist, and Ki16425, LPA1/3 receptors antagonist, but not by H2L5146303, LPA2 receptor antagonist. Pertussis toxin, Gi/o inhibitor, but not YM‐254890, Gq inhibitor, and NF499, Gs inhibitor, inhibited LPA‐induced TSP‐1 production, indicating that LPA increases TSP‐1 production through Gi/o‐coupled LPA1 and LPA3 receptors. LPA treatment increased phosphorylation of extracellular signal‐regulated kinase (ERK), p38 mitogen‐activated protein kinase (MAPK), and c‐Jun N‐terminal kinase (JNK). LPA‐induced TSP‐1 mRNA expression was inhibited by U0126, MAPK/ERK kinase (MEK) inhibitor, but not SB202190, p38 MAPK inhibitor, or SP600125, JNK inhibitor. However, LPA‐induced TSP‐1 protein expression was diminished with inhibition of all three MAPKs, indicating that these signaling molecules are involved in TSP‐1 protein production. Treatment with antidepressants, which bind to astrocytic LPA1 receptors, increased TSP‐1 mRNA and protein production. The current findings show that LPA/LPA1/3 receptors signaling increases TSP‐1 production in astrocytes, which could be important in the pathogenesis of affective disorders and could potentially be a target for the treatment of affective disorders.

Global Proteomics Analysis of Lysophosphatidic Acid Signaling in PC-3 Human Prostate Cancer Cells: Role of CCN1

“…TSP-1 is an inducible protein, and its levels have been reported to increase in response to LPA in several model systems. For example, LPA induces TSP1 at the transcriptional level in rat cortical astrocytes through the LPA receptor LPAR1 [62]. LPA has been previously shown to induce TSP1 in PC-3 cells after an 8 h treatment [63].…”

Inhibition of lysophosphatidic acid receptor 1 relieves PMN recruitment in CNS via LPA1/TSP1/CXCR2 pathway and alleviates disruption on blood-brain barrier following intracerebral haemorrhage in mice

“…Among them, LPA1 contributes heavily to the LPA network. Emerging reports suggested that LPA induces TSP1 synthesis in cortical astrocytes via LPA1 receptor activation [ 20 ].TSP1 and MIP2 are upregulated in PMN recruitment [ 35 ], MIP2 recruits PMN, and activates the CXCR2 receptor. Likewise, we also revealed that the LPA1 content in the haemorrhage hemisphere reached its peak at 24 h following ICH.…”

“…We also examined the underlying mechanism behind the LPA1-mediated enhancement of BBB integrity following ICH. Based on emerging evidence, LPA enhances TSP1 release by activating LPA1 in astrocytes [ 20 ]. TSP1 is a regulator of specific chemokines, namely, JE and MIP-2, which can increase PMN recruitment via upregulation of the CXCR2 receptor expression [ 23 , 24 , 38 ].…”

“…However, it is still unclear if LPA1 suppression preserves BBB integrity following ICH. Hisaoka-Nakashima and his team reported that LPA1 activation stimulates thrombospondin-1 (TSP1) secretion via the ERK, MAPK, JNK signaling network in astrocytes [ 20 ]. TSP1 is an extracellular matrix protein that physically associates with a myriad of ligands, namely, cell receptors, growth factors, cytokines, and proteases to modulate a numerous physio- and pathological activities [ 21 , 22 ].…”