Modulation of monocyte chemotactic protein-1 production by hyperoxia: importance of RNA stability in control of cytokine production.
Pulmonary oxygen toxicity occurs after prolonged administration of increased fractions of inspired oxygen. Lung damage in this setting manifests as diffuse alveolar damage. In animals exposed to hyperoxia, increased numbers of alveolar macrophages are noted 72 h after initiation of high concentrations of oxygen. Monocyte chemotactic protein-1 (MCP-1) is a cytokine released by a number of cell types that has potent chemotactic activity for monocytes, precursor cells for alveolar macrophages. In the current study, we examined whether MCP-1 production was increased in response to hyperoxia. We used the monocyte/ histiocytic U937 cell line and exposed these cells to hyperoxia for variable amounts of time, then determined MCP-1 concentrations by enzyme-linked immunosorbent assay and MCP-1 mRNA levels by Northern blot analysis. We also examined the effects of dexamethasone on the response of U937 cells to hyperoxia. Finally, as a potential mechanism for regulation of U937 MCP-1 production, we examined effects of hyperoxia on MCP-1 mRNA stability. The results demonstrate that hyperoxia stimulates MCP-1 production after 6 and 24 h of exposure. MCP-1 mRNA levels are also increased after initiation of hyperoxia in part through effects on MCP-1 transcript stability. Dexamethasone significantly reduces MCP-1 production and mRNA levels also in part through effects on transcript stability. These studies suggest monocytes may be attracted to hyperoxia-exposed lungs through enhanced MCP-1 production. MCP-1 production appears to be upregulated in part through post-transcriptional processes in this setting.
Cooper
J A
JA
Pulmonary Sections, Birmingham Veterans Administration Medical Center and the University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Fuller
J M
JM
McMinn
K M
KM
Culbreth
R R
RR
D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004355:Drug Stability; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D010100:Oxygen / Q000494:pharmacology*; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D014407:Tumor Cells, Cultured
D018932:Chemokine CCL2; D016207:Cytokines; D005938:Glucocorticoids; D012333:RNA, Messenger; D003907:Dexamethasone; D010100:Oxygen