Lysophosphatidic acid as a mediator for proinflammatory agonists in a human corneal epithelial cell line.
Lysophosphatidic acid (LPA) refers to a family of small phospholipid mediators that are generated in response to agonist stimulation in diverse cell types. LPA binds to G protein-coupled receptors to elicit numerous biological responses, including proliferation and inflammation. In this study, LPA production and response were characterized in a human corneal epithelial cell line, 2.040 pRSV-T. LPA levels in cells and medium are increased by exogenous 18:1 LPA (oleoyl-LPA), LPS, IL-1beta, and TNF-alpha. LPS, IL-1beta, and TNF-alpha, which mediate ocular inflammation, stimulate activation of p38, ERK, and Akt kinases in the corneal cell line. Similar responses are elicited by 18:1 LPA. Pertussis toxin (PTX) blocks LPA-induced activation of p38 and ERK but only slightly inhibits LPA-induced activation of Akt. All of the agonists tested, including LPA, stimulate proliferation of 2.040 pRSV-T cells. In these cells, both Akt and ERK pathways are important for LPA-induced proliferation. Thus PTX only partially suppresses the mitogenic response to LPA. Transcripts for the LPA receptors LPA(1)/EDG-2, LPA(2)/EDG-4, and LPA(3)/EDG-7 are expressed by the corneal cell line. Ki16425, an antagonist for LPA receptors, was used to explore the autocrine role of LPA. LPA-induced activations of p38, ERK, and Akt kinases, as well as proliferation, are inhibited by Ki16425. Ki16425 partially inhibits signal transduction and proliferation induced by the inflammatory agents tested. We conclude that LPA, produced in corneal epithelial cells in response to inflammatory agonists, contributes to mediating the mitogenic responses to these agonists in an autocrine fashion.
Zhang
Zhihong
Z
Dept. of Pharmaceutical Sciences, Washington State University, Pullman, WA 99164-6534, USA.
Liu
Zuguo
Z
Meier
Kathryn E
KE
D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003315:Cornea / Q000166:cytology* / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000819:agonists* / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008246:Lysophospholipids / Q000378:metabolism* / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D018836:Inflammation Mediators; D007375:Interleukin-1; D007555:Isoxazoles; D008070:Lipopolysaccharides; D008246:Lysophospholipids; D011422:Propionates; D012333:RNA, Messenger; D049368:Receptors, Lysophosphatidic Acid; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C032881:lysophosphatidic acid