Regulation and localization of endogenous human tristetraprolin

Arthritis Research & Therapy

Paul K Wallace¹  William Rigby⁴  Mark P Yeager²  Athos J Rassias²  Nicolas J Goulding³  Katharine A Hintz⁵  John E Connolly¹  Anna-Marie Fairhurst³ 

[1]Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH, USA

[2]Department of Anesthesiology, Dartmouth Medical School, Lebanon, NH, USA

[3]William Harvey Research Institute, University of London, London, UK

[4]Department of Medicine, Dartmouth Medical School, Lebanon, NH, USA

[5]Department of Physiology, Dartmouth Medical School, Lebanon, NH, USA

关键词: tristetraprolin;    lipopolysaccharide;    inflammation;    endotoxic shock;   

Others  :  1101371
DOI  :  10.1186/ar778

 received in 2003-02-01, accepted in 2003-04-11,  发布年份 2003

【 摘 要 】

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.

【 授权许可】

   
2003 Fairhurst et al., licensee BioMed Central Ltd

【 图 表 】

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