Ingestion of apoptotic cells in vitro by macrophages induces
TGF-beta1 secretion, resulting in an anti-inflammatory effect and suppression of proinflammatory mediators. Here, we show in vivo that direct instillation of apoptotic cells enhanced the resolution of acute
inflammation. This enhancement appeared to require
phosphatidylserine (PS) on the apoptotic cells and local induction of
TGF-beta1. Working with thioglycollate-stimulated peritonea or LPS-stimulated lungs, we examined the effect of apoptotic cell uptake on
TGF-beta1 induction. Viable or opsonized apoptotic human Jurkat T cells, or apoptotic PLB-985 cells, human monomyelocytes that do not express PS during apoptosis, failed to induce
TGF-beta1. PS
liposomes, or PS directly transferred onto the PLB-985 surface membranes, restored the
TGF-beta1 induction. Apoptotic cell instillation into LPS-stimulated lungs reduced proinflammatory
chemokine levels in the bronchoalveolar lavage fluid (BALF). Additionally, total inflammatory cell counts in the BALF were markedly reduced 1-5 days after apoptotic cell instillation, an effect that could be reversed by opsonization or coinstillation of
TGF-beta1 neutralizing antibody. This reduction resulted from early decrease in neutrophils and later decreases in lymphocytes and macrophages. In conclusion, apoptotic cell recognition and clearance, via exposure of PS and
ligation of its receptor, induce
TGF-beta1 secretion, resulting in accelerated resolution of
inflammation.