LPA induces IL-6 secretion from aortic smooth muscle cells via an LPA1-regulated, PKC-dependent, and p38alpha-mediated pathway.
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.
Hao
Feng
F
Department of Pathobiology, The University of Tennessee College of Veterinary Medicine, Knoxville, 37996, USA.
Tan
Mingqi
M
Wu
Daniel D
DD
Xu
Xuemin
X
Cui
Mei-Zhen
MZ
D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008246:Lysophospholipids / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D015850:Interleukin-6; D008246:Lysophospholipids; D012333:RNA, Messenger; D049368:Receptors, Lysophosphatidic Acid; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C032881:lysophosphatidic acid