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Volume 37, Number 1, February 2004

Pharmacological modulation of TNF production in macrophages


Hen-I Lin, Shi-Jye Chu, David Wang, Nan-Hsiung Feng
Department of Internal Medicine, Catholic Cardinal Tien Hospital, Fu-Jen Catholic University, Taipei Hsien; Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei; Department of Medicine, Fu-Jen Medical School, Fu-Jen Catholic University, Taipei Hsien; and Department of Internal Medicine, Kaohsiung Military General Hospital, Kaohsiung, Taiwan, ROC

Received: February 4, 2003    Revised: June 20, 2003    Accepted: July 4, 2003   

 

Corresponding author:

Dr. Hen-I Lin, Division of Chest Medicine, Department of Medicine, Catholic Cardinal Tien Hospital, No. 362, Chung-Cheng Road, Hsintien, Taipei Hsien, Taiwan 23137, ROC. E-mail: linlll@ms28.hinet.net This e-mail address is being protected from spam bots, you need JavaScript enabled to view it

 



 

Methods:

The quantity and duration of production of tumor necrosis factor (TNF) is tightly controlled due to its potential to cause serious harm. For example, TNF release in response to overwhelming bacterial infection has been implicated as the first step in potentially lethal septic shock. Prostaglandins and leukotrienes are thought to play opposing roles in regulating TNF production by monocytes and macrophages. We investigated the effects of 5 drugs on the production of TNF by cells of the murine macrophage line RAW264 after stimulation with bacterial lipopolysaccharide endotoxin (LPS). These drugs were of the following 3 classes: cyclooxygenase inhibitors indomethacin (indo) and ibuprofen (ibu); 5-lipoxygenase inhibitors VZ 65 and AA-861; and methylxanthine pentoxyfilline (PTX). While indo and ibu treatment resulted in increased TNF production, PTX, VZ 65, and AA-861 significantly inhibited TNF production, whether administered simultaneously with LPS or 30 min after LPS treatment. VZ 65 and AA-861 also inhibited prostaglandin E2 (PGE2) production, coupled with an absence of any rise in intracellular cAMP. Leukotriene B4 (LTB4) levels peaked at 15 min and approached background level at 30 min after LPS treatment. Taken together, these data suggest that VZ 65 and AA-861 may inhibit TNF production through mechanism(s) independent of LTB4 production. VZ 65, AA-861, and PTX all diminished the rate of TNF mRNA transcription, yet VZ 65 and AA-861 appeared to enhance message stability. We conclude that while PTX reduced TNF protein levels by inhibiting TNF mRNA transcription, both VZ 65 and AA-861 exerted opposing effects on TNF transcription and increased mRNA stability.

 



 

Key words:

Leukotrienes, lipoxygenase inhibitors, macrophages, tumor necrosis factor



 



 

J Microbiol Immunol Infect 2004;37:8-15.