Abstract
Adenosine receptor agonists have anti-inflammatory properties and modulate immune responses partly by inhibiting pro-inflammatory cytokine production by monocytes. We investigated signal transduction mechanisms by which adenosine receptor activation inhibits tumor necrosis factor-α (TNF-α) production. Phorbol-12-myristate-13-acetate (PMA) and phytohemagglutinin treatment of human pro-monocytic U937 cells increased TNF-α protein release. Activation of adenosine receptors up to 1 hr following stimulation with PMA/phytohemagglutinin significantly inhibited TNF-α protein release indicating that inhibition of TNF-α occurred post-transcriptionally. The adenosine receptor agonist 2-p-(carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680) decreased stability and half-life of PMA/phytohemagglutinin-induced TNF-α mRNA from 80 to 37 min. p38 signaling pathways control TNF-α mRNA stability in macrophages and we confirmed in our cells that p38 was involved in controlling TNF-α release post-transcriptionally. Activation of adenosine receptors with CGS 21680 decreased phospho-p38 protein levels. These data suggest that adenosine receptor activation regulates TNF-α release post-transcriptionally by decreasing mRNA stability through a mechanism involving inhibition of p38 activity.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 87-95 |
| Number of pages | 9 |
| Journal | European Journal of Pharmacology |
| Volume | 497 |
| Issue number | 1 |
| DOIs | |
| State | Published - Aug 16 2004 |
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Keywords
- Adenosine
- Monocyte
- TNF-α
- mRNA stability
- p38
ASJC Scopus subject areas
- Pharmacology
Cite this
Activation of adenosine receptors inhibits tumor necrosis factor-α release by decreasing TNF-α mRNA stability and p38 activity. / Fotheringham, Julie A.; Mayne, Michael B.; Grant, Jeffrey A.; Geiger, Jonathan D.
In: European Journal of Pharmacology, Vol. 497, No. 1, 16.08.2004, p. 87-95.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Activation of adenosine receptors inhibits tumor necrosis factor-α release by decreasing TNF-α mRNA stability and p38 activity
AU - Fotheringham, Julie A.
AU - Mayne, Michael B.
AU - Grant, Jeffrey A.
AU - Geiger, Jonathan D.
PY - 2004/8/16
Y1 - 2004/8/16
N2 - Adenosine receptor agonists have anti-inflammatory properties and modulate immune responses partly by inhibiting pro-inflammatory cytokine production by monocytes. We investigated signal transduction mechanisms by which adenosine receptor activation inhibits tumor necrosis factor-α (TNF-α) production. Phorbol-12-myristate-13-acetate (PMA) and phytohemagglutinin treatment of human pro-monocytic U937 cells increased TNF-α protein release. Activation of adenosine receptors up to 1 hr following stimulation with PMA/phytohemagglutinin significantly inhibited TNF-α protein release indicating that inhibition of TNF-α occurred post-transcriptionally. The adenosine receptor agonist 2-p-(carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680) decreased stability and half-life of PMA/phytohemagglutinin-induced TNF-α mRNA from 80 to 37 min. p38 signaling pathways control TNF-α mRNA stability in macrophages and we confirmed in our cells that p38 was involved in controlling TNF-α release post-transcriptionally. Activation of adenosine receptors with CGS 21680 decreased phospho-p38 protein levels. These data suggest that adenosine receptor activation regulates TNF-α release post-transcriptionally by decreasing mRNA stability through a mechanism involving inhibition of p38 activity.
AB - Adenosine receptor agonists have anti-inflammatory properties and modulate immune responses partly by inhibiting pro-inflammatory cytokine production by monocytes. We investigated signal transduction mechanisms by which adenosine receptor activation inhibits tumor necrosis factor-α (TNF-α) production. Phorbol-12-myristate-13-acetate (PMA) and phytohemagglutinin treatment of human pro-monocytic U937 cells increased TNF-α protein release. Activation of adenosine receptors up to 1 hr following stimulation with PMA/phytohemagglutinin significantly inhibited TNF-α protein release indicating that inhibition of TNF-α occurred post-transcriptionally. The adenosine receptor agonist 2-p-(carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680) decreased stability and half-life of PMA/phytohemagglutinin-induced TNF-α mRNA from 80 to 37 min. p38 signaling pathways control TNF-α mRNA stability in macrophages and we confirmed in our cells that p38 was involved in controlling TNF-α release post-transcriptionally. Activation of adenosine receptors with CGS 21680 decreased phospho-p38 protein levels. These data suggest that adenosine receptor activation regulates TNF-α release post-transcriptionally by decreasing mRNA stability through a mechanism involving inhibition of p38 activity.
KW - Adenosine
KW - Monocyte
KW - TNF-α
KW - mRNA stability
KW - p38
UR - http://www.scopus.com/inward/record.url?scp=4143095196&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=4143095196&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2004.06.029
DO - 10.1016/j.ejphar.2004.06.029
M3 - Article
C2 - 15321739
AN - SCOPUS:4143095196
VL - 497
SP - 87
EP - 95
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 1
ER -