Apoptotic Cells, through Transforming Growth Factor-β, 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-β (TGF-β) and anti-inflammatory eicosanoids. Here, we have investigated the role played by the induction of TGF-β in the coordinate expression of anti-inflammatory eicosanoids or peroxisome proliferator-activated receptor-γ and in the suppression of pro-inflammatory lipid mediators and nitric oxide (NO). By use of a dominant negative TGFβII receptor, TGF-β signaling was blocked, and its participation in the consequences of apoptotic cell stimulation was determined. The induction of TGF-β 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-β production. On the other hand, a requirement for TGF-β 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-β-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-γ, and lipoxin A4 production, which were also up-regulated by a TGF-β-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-β production.