LPA induces IL-6 secretion from aortic smooth muscle cells via an LPA₁-regulated, PKC-dependent, and p38α-mediated pathway

Abstract

Lysophosphatidic acid (LPA) is a potent bioactive lysophospholipid. Accumulated evidence supports a role for LPA in inflammation. To profile LPA-induced cytokine production in vascular smooth muscle cells (SMCs), we used a cytokine antibody array system and found that LPA prominently induces the secretion of IL-6 and monocyte chemoattractant protein (MCP)-1 from human aortic SMCs (HASMCs). The mechanism by which LPA induces MCP-1 expression in SMCs has been previously reported. However, LPA induction of IL-6 secretion from vascular SMCs and its regulatory mechanism are unknown. The present study reveals that LPA induces the expression of IL-6 mRNA and protein in HASMCs as well as the secretion of IL-6 protein in a time-dependent manner. Our results demonstrate that LPA-specific receptor 1 (LPA(1)) mediates LPA-induced IL-6 secretion and that LPA induction of IL-6 is independent of the EGF receptor pathway. Our data further show that PKC-mediated p38 MAPK is responsible for the IL-6 secretion. Finally, small interfering RNA depletion experiments revealed that p38alpha is specifically responsible for the LPA-induced IL-6 secretion. The present study profiles the regulatory relationship between LPA and multiple cytokines in vascular SMCs for the first time, provides the first evidence that LPA upregulates IL-6 in vascular SMCs, and reveals the regulatory mechanism of LPA-induced IL-6 production in HASMCs. In light of the emerging roles of LPA and IL-6 in vascular inflammation, the understanding of the regulatory mechanism may contribute to the treatment and prevention of cardiovascular disorders.

Lysophosphatidic Acid Induces Early Growth Response-1 (Egr-1) Protein Expression via Protein Kinase Cδ-regulated Extracellular Signal-regulated Kinase (ERK) and c-Jun N-terminal Kinase (JNK) Activation in Vascular Smooth Muscle Cells

“…To date, LPA activation of PKC, MAPK, or PKC/MAPK in various cell types (12)(13)(14)23), LPA activation of PKC␦ (24,25), and PKC␦ regulation of IL-8 expression in bronchial epithelial cells (25,26), as well as ERK involvement in LPA-induced Egr-1 expression (27), have been reported. However, the regulatory relationship between PKC␦ and MAPK in the LPA signaling pathway has not been documented.…”

Cigarette smoke extract-induced interleukin-6 expression is regulated by phospholipase D1 in human bronchial epithelial cells

“…Several reports indicate that IL-6 production and secretion increase when cells are exposed to certain conditions, such as exposure to environmental allergens, infectious stimuli, and cigarette smoke, which can result in lung inflammation, atopy, asthma (Singh et al, 2009), rheumatoid arthritis (Wei et al, 2012;Yoshida and Tanaka, 2014), lung cancer (Chen et al, 2012;Yao et al, 2014), and emphysema (Xiong et al, 2011). In addition, IL-6 production is reported to be mediated in PKC (Hao et al, 2010), MAPK (Wei et al, 2012;Schaper and Rose-John, 2015), p38MAPK (Riebe et al, 2011), JNK (Zhao et al, 2007;Al-Sadi et al, 2014;Chuang et al, 2014), NFkappaB (Chen et al, 2012;Wang et al, 2015), STAT3 (Riebe et al, 2011) and ATF2 (Park et al, 2009) dependent manners. The above study results suggest there may be a relationship between PLD and CSE-induced IL-6 expression.…”

Inhibition of lysophosphatidic acid receptor ameliorates Sjögren's syndrome in NOD mice

“…LPA/LPAR signaling has been reported to promote the production of inflammatory cytokines such as IL-1β, IL-6 [33], IL-8 [34] and TNF-α [35]. Our results showed that LPA treatment of splenocytes induced IL-17 expression, but not IFN-γ (data not shown).…”