Apoptotic cells, through transforming growth factor-beta, coordinately induce anti-inflammatory and suppress pro-inflammatory eicosanoid and NO synthesis in murine macrophages.
Apoptotic cells are rapidly engulfed by adjacent tissue cells or macrophages before they can release pro-inflammatory/proimmunogenic intracellular contents. In addition, recognition of the apoptotic cells is actively anti-inflammatory and anti-immunogenic with generation of anti-inflammatory mediators such as transforming growth factor-beta (TGF-beta) and anti-inflammatory eicosanoids. Here, we have investigated the role played by the induction of TGF-beta in the coordinate expression of anti-inflammatory eicosanoids or peroxisome proliferator-activated receptor-gamma and in the suppression of pro-inflammatory lipid mediators and nitric oxide (NO). By use of a dominant negative TGFbetaII receptor, TGF-beta signaling was blocked, and its participation in the consequences of apoptotic cell stimulation was determined. The induction of TGF-beta itself could be attributed to exposed phosphatidylserine on the apoptotic cells, which therefore appears to drive the balanced inflammatory mediator responses. Arachidonic acid release, COX-2, and prostaglandin synthase expression were shown to be significantly dependent on the TGF-beta production. On the other hand, a requirement for TGF-beta was also shown in the inhibition of thromboxane synthase and thromboxanes, of 5-lipoxygenase and sulfidopeptide leukotrienes, as well as of inducible nitric-oxide synthase and NO. TGF-beta-dependent induction of arginase was also found and would further limit the NO generation. Finally, apoptotic cells stimulated production of 15-lipoxygenase and 15-hydroxyeicosatetraenoic acid, a potentially anti-inflammatory pathway acting through peroxisome proliferator-activated receptor-gamma, and lipoxin A(4) production, which were also up-regulated by a TGF-beta-dependent pathway in this system. These results strongly suggest that the apoptotic cell inhibition of pro-inflammatory mediator production is pleiotropic and significantly dependent on the stimulation of TGF-beta production.
Freire-de-Lima
Celio G
CG
Instituto de Biofísica Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro RJ 21944-970, Brazil.
Xiao
Yi Qun
YQ
Gardai
Shyra J
SJ
Bratton
Donna L
DL
Schiemann
William P
WP
Henson
Peter M
PM
D000818:Animals; D017209:Apoptosis; D016718:Arachidonic Acid / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015777:Eicosanoids / Q000096:biosynthesis*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D019169:Jurkat Cells; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000096:biosynthesis*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology*
D015777:Eicosanoids; D018836:Inflammation Mediators; D016212:Transforming Growth Factor beta; D016718:Arachidonic Acid; D009569:Nitric Oxide; D051546:Cyclooxygenase 2