Prostaglandin E2 inhibits neutrophil extracellular trap formation through production of cyclic AMP.
OBJECTIVE
Upon stimulation, neutrophils release their nuclear contents called neutrophil extracellular traps (NETs), which contain unfolded chromatin and lysosomal enzymes. NETs have been demonstrated to play a critical role in host defence, although the role of PGE2 , a bioactive substance generated in inflammatory tissues, in the formation of NETs remains unclear.


METHODS
The effects of PGE2 , agonists and antagonists of its receptors, and modulators of the cAMP-PKA pathway on the formation of NETs were examined in vitro in isolated neutrophils and in vivo in a newly established mouse model.


RESULTS
PGE2 inhibited PMA-induced NET formation in vitro through EP2 and EP4 Gαs-coupled receptors. Incubation with a cell-permeable cAMP analogue, dibutyryl cAMP, or various inhibitors of a cAMP-degrading enzyme, PDE, also suppressed NET formation. In the assay established here, where an agarose gel was s.c. implanted in mice and NET formation was detected on the surface of the gel, the extent of the NET formed was inhibited in agarose gels containing rolipram, a PDE4 inhibitor, and butaprost, an EP2 receptor agonist.


CONCLUSIONS
PGE2 inhibits NET formation through the production of cAMP. These findings will contribute to the development of novel treatments for NETosis-related diseases.
The Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Kyosuke
K
Shishikura
The Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Takahiro
T
Horiuchi
The Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Natsumi
N
Sakata
The Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.|The Department of Oral Cancer Therapeutics, Graduate School of Dentistry, Tohoku University, Sendai, Japan.
Duc-Anh
DA
Trinh
The Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Ryutaro
R
Shirakawa
The Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Tomohiro
T
Kimura
The Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
Yujiro
Y
Asada
The Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.|The Department of Oral Cancer Therapeutics, Graduate School of Dentistry, Tohoku University, Sendai, Japan.
Hisanori
H
Horiuchi
D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis*; D015232:Dinoprostone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D065206:Extracellular Traps / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism*; D020889:Rolipram / Q000494:pharmacology
D000242:Cyclic AMP; D020889:Rolipram; D015232:Dinoprostone