EDITORIAL
Another reason for taking aspirin


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IN THIS ISSUE of the American Journal of Physiology-Lung Cellular and Molecular Physiology, Yoo et al. (17) show that the anti-inflammatory effects of high doses of acetylsalicylic acid (ASA) in lung epithelial cells include inhibition of interleukin (IL)-1beta - and tumor necrosis factor (TNF)-alpha -induced expression of IL-8. This inhibition, which is due to disruption of nuclear factor (NF)-kappa B activation, occurs at significantly higher concentrations of ASA than are needed to fully inhibit cyclooxygenase, thereby suggesting that prostanoids are not involved. NF-kappa B is an essential transcription factor regulating IL-8 expression (11). NF-kappa B activation normally relies on the phosphorylation on serine residues 32 and 36 of the inhibitor Ikappa B-alpha , which targets Ikappa B-alpha for ubiquitination and subsequent degradation (3, 4, 7). The phosphorylation of Ikappa B is catalyzed by Ikappa B kinase (IKK), which has two functional subunits (18). In their study, Yoo et al. (17) followed the trail of ASA action on TNF-alpha induction of IL-8 up the NF-kappa B pathway. ASA inhibited NF-kappa B activation in terms of translocation of the p65 subunit of NF-kappa B to the nucleus. Ikappa B-alpha degradation and phosphorylation were also inhibited. Finally, IKK activation was also shown to be inhibited by a high dose of ASA. Thus the trail of ASA action on NF-kappa B activation extends upward at least to the level of IKK activation. Because NF-kappa B plays such a central role in the transcription of cytokines, an important aspect of this work is that it provides a mechanism for the anti-inflammatory action of high-dose ASA in lung epithelial cells.

As clear as the results of the study by Yoo et al. (17) are for the action of high-dose ASA on the NF-kappa B pathway, the actual site of high-dose ASA action remains to be found. Inhibition of NF-kappa B activation by ASA was first demonstrated in 1994 (9), but the site of action remains unknown. The study by Yoo et al. (17) shows that inhibition was at least at the level of IKK. Previously, Yin et al. (16) suggested that the site of ASA and salicylic acid action was inhibition of IKK-beta . Nonetheless, earlier this year, another study (2) suggested that the inhibition by sodium salicylate of IKK activity in vitro is not responsible for its inhibition of IKK activity in intact cells. Thus inhibition of cytokine-initiated NF-kappa B activation may be even further upstream than the inhibition of IKK. Receptor binding of TNF-alpha and IL-1beta initiates a pathway of kinases and adapter protein interactions that lead to IKK activation (8). One of these may be the target of ASA action. An endogenous inhibitor of IKK called NEMO or IKK-gamma (15) could be affected by ASA, and blocking the binding of NEMO to IKK has effects similar to those of ASA (10).

Nevertheless, the specificity of drugs is well known to diminish with dose, and high-dose ASA may actually work through multiple pathways. High-dose ASA inhibits calcium mobilization and changes in cAMP independent of its effects on cyclooxygenase (1). In some systems, oxidative stress can activate or coactivate NF-kappa B with TNF-alpha (12, 13). In oxidative stress, activation of NF-kappa B may be achieved through phosphorylation of Ikappa B on a tyrosine residue, which causes its dissociation from NF-kappa B without leading to its degradation (5). Although mistakenly touted as specific hydroxyl radical scavengers, salicylates in combination with iron do act as antioxidants (6) and could thus potentially inhibit oxidant-driven NF-kappa B activation.

The use of salicylates can be traced back to the fifth century BC when Hippocrates used extracts from the willow bark to relieve pain and fever. In 1897, Felix Hoffman synthesized ASA to reduce the acidity of salicylic acid, which was thought responsible for irritation of the stomach. For the past century, ASA has remained the most commonly used drug. Its principal mode of action at low dose is the inhibition of cyclooxygenases (14); however, as discussed above, its site of action at higher doses is uncertain. Regardless of these issues, the sequence of steps for NF-kappa B activation that was investigated by Yoo et al. (17) is the best understood and probably predominant pathway for NF-kappa B activation as well as the most likely alternative site of ASA action. For inflammation in which the lung epithelium is involved, this provides a rationale for the use of high-dose ASA and for further investigation of this old but still fascinating drug.


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12.   Muroi, M, Muroi Y, and Suzuki T. The binding of immobilized IgG2a to Fc gamma 2a receptor activates NF kappaB via reactive oxygen intermediates and tumor necrosis factor alpha 1. J Biol Chem 269: 30561-30568, 1994[Abstract/Free Full Text].

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15.   Yamaoka, S, Courtois G, Bessia C, Whiteside ST, Weil R, Agou F, Kirk HE, Kay RJ, and Israel A. Complementation cloning of NEMO, a component of the Ikappa B kinase complex essential for NF-kappa B activation. Cell 93: 1231-1240, 1998[ISI][Medline].

16.   Yin, MJ, Yamamoto Y, and Gaynor RB. The anti-inflammatory agents aspirin and salicylate inhibit the activity of Ikappa B kinase-beta. Nature 396: 77-80, 1998[ISI][Medline].

17.   Yoo, C-G, Lee S, Lee C-T, Kim YW, Han SK, and Shim Y-S. Effect of acetylsalicylic acid on endogenous Ikappa B kinase activity in lung epithelial cells. Am J Physiol Lung Cell Mol Physiol 280: L3-L9, 2000[Abstract/Free Full Text].

18.   Zandi, E, Rothwarf DM, Delhase M, Hayakawa M, and Karin M. The Ikappa B kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta , necessary for Ikappa B phosphorylation and NF-kappa B activation. Cell 91: 243-252, 1997[ISI][Medline].

Henry Jay Forman,
Department of Environmental Health Sciences
School of Public Health
The University of Alabama at Birmingham
Birmingham, Alabama 35294-0022
American Journal of Physiology-
Lung Cellular and Molecular Physiology
January 2001, Volume 280 (24)


Am J Physiol Lung Cell Mol Physiol 280(1):L1-L2
1040-0605/01 $5.00 Copyright © 2001 the American Physiological Society




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