Am. J. Respir. Cell Mol. Biol., Volume 20, Number 5, May, 1999 1059-1066

Transcriptional Regulation of the Interleukin-1 Promoter via Fibrinogen Engagement of the CD18 Integrin Receptor

Rafael L. Perez, Jeffrey D. Ritzenthaler, and Jesse Roman

Pulmonary and Critical Care Division, Department of Medicine, Atlanta Veterans Affairs Medical Center, Emory University School of Medicine, Atlanta, Georgia

Fibrinogen, with or without its conversion to fibrin, in the extravascular spaces of injured and inflamed lung tissues is thought to promote inflammatory responses that can eventually lead to pulmonary fibrosis. One of these responses likely involves the elaboration of the proinflammatory cytokine interleukin (IL)- 1. We reported that both fibrinogen and fibrin stimulated production of IL-1 message and protein by binding to CD18 integrin receptors on normal human monocytes (J. Immunol., 1995;154:1879-1887). The purpose of the current work was to extend our previous observations by characterizing the transcriptional regulation of fibrinogen-induced IL-1 expression. Our model was the human monocytic cell line U937 transfected with the human IL-1 promoter connected to reporter genes. We found that fibrinogen induced the IL-1 promoter and that induction could be blocked by anti-CD18 antibody. Transfection with deletion constructs of the promoter and DNA electrophoresis mobility gel shift assays suggested that sequences containing activator protein (AP)-1, cyclic adenosine monophosphate response element (CRE), and nuclear factor (NF)-B cis-acting motifs regulate IL-1 gene expression by fibrinogen. In combination with competitive cotransfection studies using consensus oligonucleotides mimicking these motifs, we conclude that transactivation of an NF-B-like sequence is necessary for induction of the IL-1 gene, that activation of CRE may repress induction of the gene, and that AP-1 potentially modulates induction and repression of the gene induced by fibrinogen. This study begins to define the molecular mechanisms by which fibrin(ogen) promotes and regulates expression of the IL-1 gene and further substantiates a role for fibrin(ogen) in tissue injury and inflammation.

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