Cell type-specific regulation of fibrinogen expression in lung epithelial cells by dexamethasone and interleukin-1beta.
Our recent studies demonstrating the expression of fibrinogen (FBG) by an alveolar type II cell line stimulated with proinflammatory mediators and also in the inflamed pulmonary epithelium of animals with Pneumocystis carinii pneumonia suggest that extrahepatic FBG participates in the local acute phase response (APR) to infection and subsequent wound repair. However, the mechanisms that regulate extrahepatic FBG expression are poorly understood. This study compares the regulation of hepatic and pulmonary FBG expression by mediators of the APR, interleukin (IL)-6, IL-1beta, and dexamethasone (DEX), a synthetic glucocorticoid. Northern blotting and metabolic labeling studies revealed that IL-6 with or without DEX upregulates gammaFBG messenger RNA and protein, whereas IL-1beta inhibits gammaFBG expression in human lung (A549) and liver (HepG2) epithelial cells. In contrast, the addition of DEX relieved the IL-1beta-mediated inhibition of FBG expression in lung epithelial cells only; this response is termed "DEX rescue." Studies with cycloheximide indicate that only DEX rescue required de novo protein synthesis. Nuclear run-on analysis revealed no increase in gammaFBG transcription by DEX treatment. Although DEX treatment alone increased the stability of gammaFBG transcripts in lung cells, this effect was not observed in the presence of IL-1beta. Together, these results suggest that pre-existing transcription factors mediate the effects of IL-6 with or without DEX, DEX, and IL-1beta on gammaFBG gene expression in lung and liver cells. Also, the data suggest that DEX induces new protein synthesis of an inhibitor of IL-1beta signal transduction to effectively "rescue" FBG production in lung but not liver epithelial cells. This cell type-specific stimulation of FBG production by glucocorticoids to overcome IL-1beta inhibition may promote pulmonary wound repair mechanisms.
Nguyen
M D
MD
Department of Microbiology and Immunology, Department of Medicine-Vascular Medicine Unit, and Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
Simpson-Haidaris
P J
PJ
D003907:Dexamethasone / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005340:Fibrinogen / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; D003907:Dexamethasone; D005340:Fibrinogen