Search of factors that intermediate cytokine-induced group IIA phospholipase A2 expression through the cytosolic phospholipase A2- and 12/15-lipoxygenase-dependent pathway.
Inducible expression of group IIA secretory phospholipase A2 (sPLA2-IIA) by interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNFalpha) is under the control of group IVA cytosolic PLA2alpha and 12/15-lipoxygenase (12/15-LOX) in rat fibroblastic 3Y1 cells. We show here that this cytokine induction of sPLA2-IIA mRNA requires de novo protein synthesis. By means of cDNA array analysis, we found that the level of the CXC chemokine MIP-2 (macrophage inflammatory protein-2) was significantly elevated in 12/15-LOX-transfected cells compared with control cells. IL-1beta/TNFalpha-stimulated induction of endogenous MIP-2 preceded that of sPLA2-IIA, and exogenous MIP-2 induced sPLA2-IIA dose-dependently. Moreover, a MIP-2-specific antisense oligonucleotide and small interfering RNA attenuated the IL-1beta/TNFalpha-induced expression of sPLA2-IIA, suggesting that MIP-2 is an absolute intermediate requirement for optimal induction of sPLA2-IIA. In addition, the expression of c-jun and fra-1, which are components of the transcription factor AP-1, was elevated in 12/15-LOX-transfected cells, in which cytokine-dependent binding of AP-1 to the sPLA2-IIA promoter was increased significantly. Conversely, the receptors for transforming growth factor-beta and platelet-derived growth factor, which contributed to down-regulation of sPLA2-IIA expression, were decreased following 12/15-LOX overexpression. Taken together, 12/15-LOX-dependent up-regulation of sPLA2-IIA expression may result from the interplay between accelerated MIP-2 signaling, AP-1 activation, and attenuated transforming growth factor-beta and platelet-derived growth factor signaling.
Kuwata
Hiroshi
H
Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Tokyo 142-8555, Japan.
Nonaka
Takuya
T
Murakami
Makoto
M
Kudo
Ichiro
I
D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D054426:Chemokine CXCL2; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D054501:Group II Phospholipases A2; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D016376:Oligonucleotides, Antisense; D010741:Phospholipases A / Q000235:genetics* / Q000378:metabolism*; D054467:Phospholipases A2; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C475064:12-15-lipoxygenase; D054426:Chemokine CXCL2; D019743:Chemokines, CXC; C513296:Cxcl2 protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2