Interleukin‐6‐induced plasminogen gene expression in murine hepatocytes is mediated by transcription factor CCAAT/enhancer binding protein β (C/EBPβ)

Abstract

Summary. An emerging area of research has demonstrated that plasminogen functions in the acute-phase response to tissue injury, neoplastic growth or infection. We have previously shown that the acute-phase mediator, interleukin (IL)-6, increases circulating plasminogen levels via upregulation of plasminogen promoter activity. We also identified a putative IL-6 responsive element (nt )791 to )783; IL6-RE) in the plasminogen gene that is required for maximal stimulation of promoter activity by IL-6. For the present study, we investigated the transcription factors and signaling pathway mediating the response of the plasminogen gene to IL-6. In electrophoretic mobility shift assays (EMSAs), a radiolabeled oligonucleotide IL6-RE probe formed specific complexes with nuclear proteins from untreated hepatocytic cells. The extent of complex formation was markedly increased using nuclear proteins from IL-6-treated cells. Complex formation was abolished by an oligonucleotide with the consensus CCAAT/enhancer binding protein (C/EBP) sequence. Furthermore, complexes were supershifted by antibodies to C/EBPb. Treatment of Hepa 1-6 cells with the mitogen-activated protein kinase (MAPK) inhibitor, PD-98059, inhibited IL-6-stimulated plasminogen promoter activity. These results suggest that transcription factor C/EBPb and the MAPK pathway play key roles in the response of the plasminogen gene to IL-6, thus elucidating a major mechanism by which the plasminogen system is upregulated to perform its crucial functions in the acutephase response.

Genetic variants in PLG, LPA, and SIGLEC 14 as well as smoking contribute to plasma plasminogen levels

“…36 Indeed, previous studies have shown that the PLG gene contains acute-phase responsive elements, which may provide a mechanistic explanation of increased PLG levels in smokers. 37 Consistent with our findings, smoking appears to be associated with an increase in C-reactive protein, a classic acutephase reactant, in a study of adolescents. The strongest genetic association for PLG levels was with a nonsynonymous SNP, rs4252129, in the PLG gene itself, with a MAF of 1.4% in GABC and 2.2% in TSS.…”

Plasminogen inhibits TNFα-induced apoptosis in monocytes

“…6 In addition, elevated levels of ␣ 2 -antiplasmin are detected in synovial fluid of affected joints in patients with arthritis. 7 Furthermore, in response to inflammatory cytokines the plasminogen gene is up-regulated, [8][9][10][11] leading to increased circulating levels of plasminogen. 8 An emerging area of research strongly supports a role for the plasminogen activation system in regulation of apoptosis.…”

Hemostatic Soluble Plasma Proteins During Acute-Phase Response and Chronic Inflammation

“…Interestingly, IL-6-REs were identified in human CRP and 2 -macroglobulin genes, as well as in two genes responsible for synthesis of fibrinogen -and ß-chains. The same IL-6-REs is located in the region identified as a cytokine-response region of murine Pg and human PAI-1 (Bannach et al, 2004;Loppnow & Libby, 1990). More than one IL-6-RE can exist in the promoter region required for the full responsiveness to IL-6.…”

“…Under transcriptional control by the cytokine IL-6, their circulating levels increase via cooperative up-regulation of the corresponding gene promoter activity. The congruence of the HSPP gene responses to IL-6 is provided by an IL-6-responsive element (IL6-RE) that is required for maximal stimulation of the promoter activity by IL-6 (Bannach et al, 2004). Interestingly, IL-6-REs were identified in human CRP and 2 -macroglobulin genes, as well as in two genes responsible for synthesis of fibrinogen -and ß-chains.…”