Interleukin-1beta gene transcription in U937 cells is modulated by type I collagen and cytoskeletal integrity via distinct signaling pathways.
Type I collagen (Col), an extracellular matrix molecule highly expressed in injured tissues, stimulates interleukin-1beta (IL-1beta) expression in monocytic cells. Using U937 cells transfected with the human IL-1beta gene promoter connected to a reporter gene, we examined how the organizational state of the cytoskeleton modulates the expression of IL-1beta after Col stimulation. We found the same degree of stimulation of IL-1beta gene transcription in cells exposed to Col presented in different fashions (i.e., soluble Col, Col-coated plate, three-dimensional Col lattice), suggesting that stimulation of IL-1beta is independent of the mode of presentation of Col. The Col-stimulated response was associated with induction of the transcription factor activator protein-1 (AP-1) and was abolished by a protein kinase C (PKC) inhibitor, by a mitogen-activated protein kinase (MAPK) inhibitor, and by cotransfection of cells with a competing AP-1 oligo. Disruption of cytoskeletal organization with colchicine or cytochalasin B stimulated IL-1beta gene transcription and enhanced the cells' response to Col. The effects of cytochalasin and colchicine were inhibited by the PKC inhibitor but were not affected by the MAPK inhibitor or the AP-1 oligo. These findings suggest that the cytoskeletal integrity modulates the constitutive and Col-stimulated transcription of the IL-1beta gene via distinct signaling mechanisms.
Pulmonary & Critical Care Division, Department of Medicine, Atlanta Veterans Affairs Medical Center and Emory University School of Medicine, Atlanta, GA 30033, USA.
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JD
Ritzenthaler
J
J
Roman
D003078:Colchicine / Q000494:pharmacology; D003094:Collagen / Q000378:metabolism / Q000494:pharmacology*; D003571:Cytochalasin B / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics*; D048369:MAP Kinase Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D020298:U937 Cells
D007375:Interleukin-1; D009281:Naphthalenes; D003571:Cytochalasin B; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; C058819:calphostin C; D003078:Colchicine