Role of acylglycerol kinase in LPA-induced IL-8 secretion and transactivation of epidermal growth factor-receptor in human bronchial epithelial cells.
LPA (lysophosphatidic acid) is a potent bioactive phospholipid, which regulates a number of diverse cellular responses through G protein-coupled LPA receptors. Intracellular LPA is generated by the phosphorylation of monoacylglycerol by acylglycerol kinase (AGK); however, the role of intracellular LPA in signaling and cellular responses remains to be elucidated. Here, we investigated signaling pathways of IL-8 secretion mediated by AGK and intracellular LPA in human bronchial epithelial cells (HBEpCs). Expression of AGK in HBEpCs was detected by real-time PCR, and overexpressed AGK was mainly localized in mitochondria as determined by immunofluorescence and confocal microscopy. Overexpression of lentiviral AGK wild type increased intracellular LPA production ( approximately 1.8-fold), enhanced LPA-mediated IL-8 secretion, and stimulated tyrosine phosphorylation epidermal growth factor-receptor (EGF-R). Furthermore, downregulation of native AGK by AGK small interfering RNA decreased intracellular LPA levels ( approximately 2-fold) and attenuated LPA-induced p38 MAPK, JNK, and NF-kappaB activation, tyrosine phosphorylation of EGF-R, and IL-8 secretion. These results suggest that native AGK regulates LPA-mediated IL-8 secretion involving MAPKs, NF-kappaB, and transactivation of EGF-R. Thus AGK may play an important role in innate immunity and airway remodeling during inflammation.
Kalari
Satish
S
Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, Chicago, Illinois, USA.
Zhao
Yutong
Y
Spannhake
Ernst Wm
EW
Berdyshev
Evgeny V
EV
Natarajan
Viswanathan
V
D001483:Base Sequence; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology; D066246:ErbB Receptors / Q000235:genetics*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013347:Subcellular Fractions / Q000201:enzymology; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
C508606:CXCL8 protein, human; D017931:DNA Primers; D016209:Interleukin-8; D008246:Lysophospholipids; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C492429:AGK protein, human; D017853:Phosphotransferases (Alcohol Group Acceptor); D066246:ErbB Receptors; C032881:lysophosphatidic acid