HỌC TỐT TIẾNG ANH 11 THEO CHƯƠNG TRÌNH GLOBAL SUCCESS ĐÁP ÁN CHI TIẾT - CẢ NĂ...
Bioactive lipids, montreal sept 2007
1. Aspirin-triggered lipoxins override the apoptosis
delaying action of serum amyloid A in human
neutrophils: A novel mechanism for resolution of
inflammation
János G. Filep,1
Levente Jozsef,1
Tarek Khreiss,1
Wanling Pan,1
Nicos A. Petasis,2
Charles N. Serhan,3
and Driss El Kebir1
1
Research Center, Maisonneuve-Rosemont Hospital,
University of Montreal, Montreal, QC, Canada H1T 2M4
2
Department of Chemistry, University of Southern California, Los Angeles, CA 90089
3
Center for Experimental Therapeutics and Reperfusion Injury,
Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02155
2. Serum amyloid A
• Marker of inflammation
• Classical acute-phase protein
• Serum concentration: <1 µg/mL to 1000 µg/mL
• Prognostic factor in rheumatoid arthritis and unstable angina
• Can be detected in inflamed tissues
• Activates neutrophils
• Undergo constitutive apoptosis
• Can be rescued from cell death by pro-inflammatory mediators
• Suppressed neutrophil apoptosis is a characteristic feature of
rheumatoid arthritis and unstable angina
Neutrophils
3. Aims
• whether SAA modulates constitutive neutrophil apoptosis
• what signaling events are associated with this event
• whether such actions can be influenced by aspirin-
triggered 15-epi-LXA4
5. SAA signals through ALXRSAA signals through ALXR
SAA
ALXR
** P<0.01
n = 5
24 h culture
N-t-Boc-Phe-Leu-Phe-Leu-Phe (Boc2):
antagonist of the fMLP receptor and ALXR
6. Activation of Akt and ERKActivation of Akt and ERK
AktERK
PI-3kMEK
SAA
ALXR
SAA: 10 µg/ml
7. Blockade of Akt and ERK reversesBlockade of Akt and ERK reverses
the SAA actionsthe SAA actions
AktERK
PI-3kMEK
SAA
ALXR
n = 5-7
** P<0.01 vs. untreated
††
P<0.01 vs. SAA
24 h culture
8. p p
BAD
p p
Mcl-1
BAD Mcl-1
AktERK
PI 3kMEK
SAA
ALX
Phosphorylation of BAD
Challenge: SAA, 10 µg/ml for 30 min
19. Conclusions
• Our results provide evidence for a mechanism by which SAA may
contribute to inflammation by rescuing neutrophils from apoptosis.
• SAA suppresses neutrophil apoptosis by preventing mitochondrial
dysfunction and consequently inhibiting cytochrome c release and
caspase-3 activation.
• 15-epi-LXA4 overrides the apoptosis delaying signals activated by
SAA and thus redirecting neutrophils to apoptosis, consistent with
facilitation of the resolution of inflammation.
20. Filep lab
Levente József
Tarek Khreiss
Driss El Kebir
Wanling Pan
Janos G. Filep
Flow cytometry lab
Sophie Ouellette
Chantal Baron
Blood donors
Collaborators
Lawrence A. Potempa (Immtech International)
John S.D. Chan (CR-CHUM)
Charles N. Serhan (Harvard University)
Nicos A. Petasis (U. of Southern California)
Acknowledgements
30. Formyl-peptide receptors
• FPR: high affinity receptor for fMLP
• FPLR1/ALXR: low affinity receptor for
fMLP plus many other ligands
• FPLR2: does not bind fMLP, ligands?
SAA is one of the classical acute phase proteins, and like C-reactive protein it is produced and secreted by the liver. serum concentration of SAA is below 1ug/ml in healthy subjects and could rise up to 1000ug/ml. SAA is used as prognostic factor in rheumatoid arthritis and in unstable angina. SAA was also detected at inflamed tissues. Surprisingly little is known of biological actions of SAA. There is evidence that SAA stimulates cytokines release from human neutrophils chemotaxis and promotes neutrophil adhesion to endothelial cells. Neutrophil activation is intimately linked to prolonged survival, a critical event in inflammation PMN have s short life span and die via apoptosis. However, pro-inflammatory mediators can rescue pmn from program cell death, for instance, RA and instable angina are associated with suppressed neutrophil apoptosis. Therefore we asked
An intriguing aspect of SAA biology is that its actions are mediated by a pleiotropic receptor, the lipoxin receptor. As I have shown SAA supresses the apoptotic machinery.Another ligand to the same receptor, annexin-1 was reported to accelerate neutrophil apoptosis, whereas the lipid mediators LXA4 and ATL by themselves had no effect on neutrophil fate. However, we have data indicating that they can override the antiapoptosis action of SAA and promotes resolution of inflammation. These findings add to the complexitiy of the biology of the LXAR, but also suggest a therapeutic potential for LXA4 and ATL when SAA formation is enhanced.