Abstract
The efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) is considered to be a result of their inhibitory effect on cyclooxygenase (COX) activity. Here, we report that flufenamic acid shows two opposing effects on COX-2 expression; it induces COX-2 expression in the colon cancer cell line (HT-29) and macrophage cell line (RAW 264.7); conversely, it inhibits tumor necrosis factor α (TNFα)- or lipopolysaccharide (LPS)-induced COX-2 expression. This inhibition correlates with the suppression of TNFα- or LPS-induced NFκB activation by flufenamic acid. The inhibitor of extracellular signal-regulated protein kinase, p38, or NFκB does not affect the NSAID-induced COX-2 expression. These results suggest that the NSAID-induced COX-2 expression is not mediated through activation of NFκB and mitogen-activated protein kinases. An activator of peroxisome proliferator-activated receptor γ, 15-deoxy-Δ12,14-prostaglandin J2, also induces COX-2 expression and inhibits TNFα-induced NFκB activation and COX-2 expression. Flufenamic acid and 15-deoxy-Δ12,14-prostaglandin J2 also inhibit LPS-induced expression of inducible form of nitric-oxide synthase and interleukin-1α in RAW 264.7 cells. Together, these results indicate that the NSAIDs inhibit mitogen-induced COX-2 expression while they induce COX-2 expression. Furthermore, the results suggest that the anti-inflammatory effects of flufenamic acid and some other NSAIDs are due to their inhibitory action on the mitogen-induced expression of COX-2 and downstream markers of inflammation in addition to their inhibitory effect on COX enzyme activity.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 28173-28179 |
| Number of pages | 7 |
| Journal | Journal of Biological Chemistry |
| Volume | 275 |
| Issue number | 36 |
| DOIs | |
| State | Published - Sep 8 2000 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Biochemistry
Cite this
Two opposing effects of non-steroidal anti-inflammatory drugs on the expression of the inducible cyclooxygenase : Mediation through different signaling pathways. / Paik, Ji H.; Ju, Jeong H.; Lee, Joo Y.; Boudreau, Mary D.; Hwang, Daniel H.
In: Journal of Biological Chemistry, Vol. 275, No. 36, 08.09.2000, p. 28173-28179.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Two opposing effects of non-steroidal anti-inflammatory drugs on the expression of the inducible cyclooxygenase
T2 - Mediation through different signaling pathways
AU - Paik, Ji H.
AU - Ju, Jeong H.
AU - Lee, Joo Y.
AU - Boudreau, Mary D.
AU - Hwang, Daniel H.
PY - 2000/9/8
Y1 - 2000/9/8
N2 - The efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) is considered to be a result of their inhibitory effect on cyclooxygenase (COX) activity. Here, we report that flufenamic acid shows two opposing effects on COX-2 expression; it induces COX-2 expression in the colon cancer cell line (HT-29) and macrophage cell line (RAW 264.7); conversely, it inhibits tumor necrosis factor α (TNFα)- or lipopolysaccharide (LPS)-induced COX-2 expression. This inhibition correlates with the suppression of TNFα- or LPS-induced NFκB activation by flufenamic acid. The inhibitor of extracellular signal-regulated protein kinase, p38, or NFκB does not affect the NSAID-induced COX-2 expression. These results suggest that the NSAID-induced COX-2 expression is not mediated through activation of NFκB and mitogen-activated protein kinases. An activator of peroxisome proliferator-activated receptor γ, 15-deoxy-Δ12,14-prostaglandin J2, also induces COX-2 expression and inhibits TNFα-induced NFκB activation and COX-2 expression. Flufenamic acid and 15-deoxy-Δ12,14-prostaglandin J2 also inhibit LPS-induced expression of inducible form of nitric-oxide synthase and interleukin-1α in RAW 264.7 cells. Together, these results indicate that the NSAIDs inhibit mitogen-induced COX-2 expression while they induce COX-2 expression. Furthermore, the results suggest that the anti-inflammatory effects of flufenamic acid and some other NSAIDs are due to their inhibitory action on the mitogen-induced expression of COX-2 and downstream markers of inflammation in addition to their inhibitory effect on COX enzyme activity.
AB - The efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) is considered to be a result of their inhibitory effect on cyclooxygenase (COX) activity. Here, we report that flufenamic acid shows two opposing effects on COX-2 expression; it induces COX-2 expression in the colon cancer cell line (HT-29) and macrophage cell line (RAW 264.7); conversely, it inhibits tumor necrosis factor α (TNFα)- or lipopolysaccharide (LPS)-induced COX-2 expression. This inhibition correlates with the suppression of TNFα- or LPS-induced NFκB activation by flufenamic acid. The inhibitor of extracellular signal-regulated protein kinase, p38, or NFκB does not affect the NSAID-induced COX-2 expression. These results suggest that the NSAID-induced COX-2 expression is not mediated through activation of NFκB and mitogen-activated protein kinases. An activator of peroxisome proliferator-activated receptor γ, 15-deoxy-Δ12,14-prostaglandin J2, also induces COX-2 expression and inhibits TNFα-induced NFκB activation and COX-2 expression. Flufenamic acid and 15-deoxy-Δ12,14-prostaglandin J2 also inhibit LPS-induced expression of inducible form of nitric-oxide synthase and interleukin-1α in RAW 264.7 cells. Together, these results indicate that the NSAIDs inhibit mitogen-induced COX-2 expression while they induce COX-2 expression. Furthermore, the results suggest that the anti-inflammatory effects of flufenamic acid and some other NSAIDs are due to their inhibitory action on the mitogen-induced expression of COX-2 and downstream markers of inflammation in addition to their inhibitory effect on COX enzyme activity.
UR - http://www.scopus.com/inward/record.url?scp=0034623141&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034623141&partnerID=8YFLogxK
U2 - 10.1074/jbc.M002329200
DO - 10.1074/jbc.M002329200
M3 - Article
VL - 275
SP - 28173
EP - 28179
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 36
ER -