Induction of urokinase-type plasminogen activator receptor by IL-1 beta.
Extensive tissue remodeling occurs in survivors of acute lung injury, leading to nearly normal histology and physiology in the majority of individuals, whereas others suffer significant impairment due to the development of pulmonary fibrosis. Alveolar epithelial cells play a central role in the repair process. They are strategically located to directly participate in the solubilization of intraalveolar fibrin deposits, and have the capacity to promote fibrinolysis. We have previously reported that interleukin-1 beta (IL-1 beta), an important inflammatory mediator in acute lung injury, upregulates urokinase-type plasminogen activator expression by human A549 cells (1). In this work, we show that IL-1 beta increases cell-surface plasmin generation, mediated in part by increased expression of urokinase receptor (u-PAR). Northern blot analyses demonstrated that IL-1 beta rapidly induces accumulation of u-PAR messenger RNA (mRNA) in a dose-dependent fashion, and that this effect is blocked by actinomycin. The IL-1 beta-mediated increase in u-PAR mRNA is inhibited by: (1) the relatively specific protein kinase C (PKC) inhibitors 1-(5-isoquinoline sulfonyl)-2-methylpiperazine (H7) and calphostin C; and (2) prolonged pretreatment of cells with phorbol myristate acetate (PMA), suggesting that PKC is an important component of the signaling pathway. Okadaic acid, an inhibitor of serine/threonine phosphatases, markedly potentiates the effect of IL-1 beta on u-PAR mRNA levels. In contrast, dexamethasone, in concentrations as low as 10(-8) M, completely blocks the IL-1 beta-mediated increase in u-PAR mRNA. Half-life experiments show that dexamethasone has no effect on u-PAR mRNA stability. Aldosterone, at concentrations in which it binds primarily to the mineralocorticoid receptor, has no effect on u-PAR expression, suggesting that the glucocorticoid effect is due to a transrepressive mechanism. In summary, IL-1 beta increases cell-surface plasmin generation in A549 cells by coordinately upregulating urokinase and u-PAR expression. Transcriptional activation of the u-PAR gene involves PKC-dependent mechanisms, and glucocorticoid suppression is probably due to interactions between the glucocorticoid receptor and another transcriptional activating system such as activator protein-1 (AP-1) and/or nuclear factor-kB (NF-kB).
Hasegawa
T
T
Salt Lake Veterans Administration Medical Center, Salt Lake City, Utah, USA.
Sorensen
L
L
Dohi
M
M
Rao
N V
NV
Hoidal
J R
JR
Marshall
B C
BC
D015152:Blotting, Northern; D002478:Cells, Cultured; D004847:Epithelial Cells; D004848:Epithelium / Q000737:chemistry / Q000201:enzymology; D005341:Fibrinolysin / Q000096:biosynthesis / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D008168:Lung / Q000737:chemistry / Q000166:cytology*; D016328:NF-kappa B / Q000378:metabolism; D010960:Plasminogen Activators / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D015398:Signal Transduction / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
D005938:Glucocorticoids; D018836:Inflammation Mediators; D007375:Interleukin-1; D016328:NF-kappa B; C524898:PLAUR protein, human; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011965:Receptors, Glucocorticoid; D055293:Receptors, Urokinase Plasminogen Activator; D018808:Transcription Factor AP-1; D011493:Protein Kinase C; D010960:Plasminogen Activators; D005341:Fibrinolysin