期刊
ARTHRITIS RESEARCH & THERAPY
卷 5, 期 4, 页码 R214-R225出版社
BIOMED CENTRAL LTD
DOI: 10.1186/ar778
关键词
endotoxic shock; inflammation; lipopolysaccharide; tristetraprolin
类别
资金
- NATIONAL CENTER FOR RESEARCH RESOURCES [P20RR016437] Funding Source: NIH RePORTER
- NCI NIH HHS [P30 CA023108] Funding Source: Medline
- NCRR NIH HHS [P20 RR16437, P20 RR016437] Funding Source: Medline
- NIAID NIH HHS [T32 AI007363] Funding Source: Medline
- NIAMS NIH HHS [T32 AR007576] Funding Source: Medline
Tumor necrosis factor (TNF) has been implicated in the development and pathogenicity of infectious diseases and autoimmune disorders, such as septic shock and arthritis. The zinc-finger protein tristetraprolin (TTP) has been identified as a major regulator of TNF biosynthesis. To define its intracellular location and examine its regulation of TNF, a quantitive intracellular staining assay specific for TTP was developed. We establish for the first time that in peripheral blood leukocytes, expression of endogenous TTP is confined to the cytoplasm. Baseline expression of TTP was higher in monocytes than in lymphocytes or neutrophils. After in vitro incubation with lipopolysaccharide (LPS), leukocyte TTP levels increased rapidly, peaking after approximately 2 hours. Monocytes showed the greatest response to LPS stimulation and lymphocytes the least. TTP levels were also studied in leukocytes isolated from healthy volunteers infused with a bolus dose of LPS. TTP expression and initial upregulation in response to LPS infusion were consistent with the in vitro data. Neutrophil TTP levels responded first, reaching an initial peak within 1 hour, monocyte levels peaked next at 2 hours, followed by lymphocytes at 4 hours. This response paralleled plasma TNF levels, which peaked 2 hours after infusion and were no longer detectable after 12 hours. A second rise in intracellular TTP levels, which did not parallel plasma TNF levels, was observed in all leukocyte populations, starting 12 hours after infusion. These data establish the cytoplasmic location of TTP, supporting a major role for this protein in regulating TNF production, and suggest that TTP levels are not regulated solely by TNF.
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