Cyclooxygenase-2 generates anti-inflammatory mediators from omega-3 fatty acids
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Cyclooxygenase-2 generates anti-inflammatory mediators from omega-3 fatty acids. / Groeger, Alison L; Cipollina, Chiara; Cole, Marsha P; Woodcock, Steven R; Bonacci, Gustavo; Rudolph, Tanja K; Rudolph, Volker; Freeman, Bruce A; Schopfer, Francisco J.
in: NAT CHEM BIOL, Jahrgang 6, Nr. 6, 06.2010, S. 433-441.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Cyclooxygenase-2 generates anti-inflammatory mediators from omega-3 fatty acids
AU - Groeger, Alison L
AU - Cipollina, Chiara
AU - Cole, Marsha P
AU - Woodcock, Steven R
AU - Bonacci, Gustavo
AU - Rudolph, Tanja K
AU - Rudolph, Volker
AU - Freeman, Bruce A
AU - Schopfer, Francisco J
PY - 2010/6
Y1 - 2010/6
N2 - Electrophilic fatty acids are generated during inflammation by non-enzymatic reactions and can modulate inflammatory responses. We used a new mass spectrometry-based electrophile capture strategy to reveal the formation of electrophilic oxo-derivatives (EFOX) from the omega-3 fatty acids docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA). These EFOX were generated by a cyclooxygenase-2 (COX-2)-catalyzed mechanism in activated macrophages. Modulation of COX-2 activity by aspirin increased the rate of EFOX production and their intracellular levels. Owing to their electrophilic nature, EFOX adducted to cysteine and histidine residues of proteins and activated Nrf2-dependent anti-oxidant gene expression. We confirmed the anti-inflammatory nature of DHA- and DPA-derived EFOX by showing that they can act as peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists and inhibit pro-inflammatory cytokine and nitric oxide production, all within biological concentration ranges. These data support the idea that EFOX are signaling mediators that transduce the beneficial clinical effects of omega-3 fatty acids, COX-2 and aspirin.
AB - Electrophilic fatty acids are generated during inflammation by non-enzymatic reactions and can modulate inflammatory responses. We used a new mass spectrometry-based electrophile capture strategy to reveal the formation of electrophilic oxo-derivatives (EFOX) from the omega-3 fatty acids docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA). These EFOX were generated by a cyclooxygenase-2 (COX-2)-catalyzed mechanism in activated macrophages. Modulation of COX-2 activity by aspirin increased the rate of EFOX production and their intracellular levels. Owing to their electrophilic nature, EFOX adducted to cysteine and histidine residues of proteins and activated Nrf2-dependent anti-oxidant gene expression. We confirmed the anti-inflammatory nature of DHA- and DPA-derived EFOX by showing that they can act as peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists and inhibit pro-inflammatory cytokine and nitric oxide production, all within biological concentration ranges. These data support the idea that EFOX are signaling mediators that transduce the beneficial clinical effects of omega-3 fatty acids, COX-2 and aspirin.
KW - Anti-Inflammatory Agents/chemical synthesis
KW - Borohydrides/pharmacology
KW - Cell Line
KW - Cell Membrane/metabolism
KW - Cyclooxygenase 2/metabolism
KW - Docosahexaenoic Acids/chemistry
KW - Fatty Acids, Omega-3/metabolism
KW - Fatty Acids, Unsaturated/metabolism
KW - Glutathione/metabolism
KW - Humans
KW - Hydroxylation
KW - Interleukin-10/genetics
KW - Interleukin-6/genetics
KW - Macrophages/drug effects
KW - PPAR gamma/metabolism
U2 - 10.1038/nchembio.367
DO - 10.1038/nchembio.367
M3 - SCORING: Journal article
C2 - 20436486
VL - 6
SP - 433
EP - 441
JO - NAT CHEM BIOL
JF - NAT CHEM BIOL
SN - 1552-4450
IS - 6
ER -