![]() |
ARTICLE |
---|
![]() ![]() ![]() |
---|
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)-1- and tumor necrosis factor
(TNF)-
-induced expression of IL-8. This inhibition, which is due to
disruption of nuclear factor (NF)-
B activation, occurs at
significantly higher concentrations of ASA than are needed to fully
inhibit cyclooxygenase, thereby suggesting that prostanoids are not
involved. NF-
B is an essential transcription factor regulating IL-8
expression (11). NF-
B activation normally relies on the
phosphorylation on serine residues 32 and 36 of the inhibitor
I
B-
, which targets I
B-
for ubiquitination and subsequent
degradation (3, 4, 7). The phosphorylation of I
B is
catalyzed by I
B kinase (IKK), which has two functional subunits
(18). In their study, Yoo et al. (17)
followed the trail of ASA action on TNF-
induction of IL-8 up the
NF-
B pathway. ASA inhibited NF-
B activation in terms of
translocation of the p65 subunit of NF-
B to the nucleus. I
B-
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-
B activation extends upward at least
to the level of IKK activation. Because NF-
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-B pathway, the actual site of high-dose ASA action remains to be found. Inhibition of NF-
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-
.
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-
B activation may be
even further upstream than the inhibition of IKK. Receptor binding of
TNF-
and IL-1
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-
(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-B with
TNF-
(12, 13). In oxidative stress, activation of
NF-
B may be achieved through phosphorylation of I
B on a tyrosine
residue, which causes its dissociation from NF-
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-
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-B activation that was
investigated by Yoo et al. (17) is the best understood and
probably predominant pathway for NF-
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.
![]() |
REFERENCES |
---|
![]() ![]() ![]() |
---|
1.
Abramson, S,
Korchak H,
Ludewig R,
Edelson H,
Haines K,
Levin RI,
Herman R,
Rider L,
Kimmel S,
and
Weissmann G.
Modes of action of aspirin-like drugs.
Proc Natl Acad Sci USA
82:
7227-7231,
1985[Abstract].
2.
Alpert, D,
and
Vilcek J.
Inhibition of IB kinase activity by sodium salicylate in vitro does not reflect its inhibitory mechanism in intact cells.
J Biol Chem
275:
10925-10929,
2000
3.
Baldwin, ASJ
The NF-kB and IkB proteins: new discoveries and insights.
Annu Rev Immunol
14:
649-681,
1996[ISI][Medline].
4.
Ghosh, S,
and
Baltimore D.
Activation in vitro of NF-kB by phosphorylation of its inhibitor IkB.
Nature
344:
678-682,
1990[ISI][Medline].
5.
Imbert, V,
Rupec RA,
Livolsi A,
Pahl HL,
Traencker EBM,
Mueller-Dieckmann C,
Farhifar DRB,
Auberger P,
Baeuerle PA,
and
Peyron JF.
Tyrosine phosphorylation of IkB- activates NF-kB without proteolytic degradation of IkB-
.
Cell
86:
787-798,
1996[ISI][Medline].
6.
Jay, D,
Jay EG,
and
Medina MA.
Superoxide dismutase activity of the salicylate-iron complex.
Arch Med Res
30:
93-96,
1999[ISI][Medline].
7.
Karin, M,
and
Ben-Neriah Y.
Phosphorylation meets ubiquitination: the control of NF-B activity.
Annu Rev Immunol
18:
621-663,
2000[ISI][Medline].
8.
Karin, M,
and
Delhase M.
The IB kinase (IKK) and NF-
B: key elements of proinflammatory signalling.
Semin Immunol
12:
85-98,
2000[ISI][Medline].
9.
Kopp, E,
and
Ghosh S.
Inhibition of NFkB by sodium salicylate and aspirin.
Science
265:
956-959,
1994[ISI][Medline].
10.
May, MJ,
D'Acquisto F,
Madge LA,
Glockner J,
Pober JS,
and
Ghosh S.
Selective inhibition of NF-B activation by a peptide that blocks the interaction of NEMO with the I
B kinase complex.
Science
289:
1550-1554,
2000
11.
Mukaida, N,
Okamoto S,
Ishikawa Y,
and
Matsushima K.
Molecular mechanism of interleukin-8 gene expression.
J Leukoc Biol
56:
554-558,
1994[Abstract].
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
13.
Schreck, R,
Rieber P,
and
Baeuerle PA.
Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kB transcription factor and HIV-1.
EMBO J
10:
2247-2258,
1991[Abstract].
14.
Vane, JR.
Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs.
Nat New Biol
231:
232-235,
1971[ISI][Medline].
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 IB kinase complex essential for NF-
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 IB 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 IB kinase activity in lung epithelial cells.
Am J Physiol Lung Cell Mol Physiol
280:
L3-L9,
2000
18.
Zandi, E,
Rothwarf DM,
Delhase M,
Hayakawa M,
and
Karin M.
The IB kinase complex (IKK) contains two kinase subunits, IKK
and IKK
, necessary for I
B phosphorylation and NF-
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) |
HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Visit Other APS Journals Online |