MACROPHAGES THAT HAVE INGESTED APOPTOTIC CELLS IN-VITRO INHIBIT PROINFLAMMATORY CYTOKINE PRODUCTION THROUGH AUTOCRINE PARACRINE MECHANISMS INVOLVING TGF-BETA, PGE2, AND PAF/

Apoptosis in vivo is followed almost inevitably by rapid up-take into adjacent phagocytic cells, a critical process in tissue remodeling, re gulation of the immune response, car resolution of inflammation. Phago cytosis of apoptotic cells by macrophages has been suggested to be a q uiet process that does Plot lead to production of inflammatory mediato rs, Here we show that phagocytosis of apoptotic neutrophils (in contra st to immunoglobulin G-opsonized apoptotic cells) actively inhibited t he production of interleukin (IL)-1 beta, IL-8, IL-10, granulocyte mac rophage colony-stimulating factor, and tumor necrosis factor-alpha, as well as leukotriene C-4 and thromboxane B2, by human monocyte-derived macrophages. In contrast, production of transforming growth factor (T GF)-beta 1, prostaglandin E2, and platelet-activating factor (PAF) was increased, The latter appeared to be involved in the inhibition of pr oinflammatory cytokine production because addition of exogenous TGF-be ta 1, prostaglandin E2, or PAF resulted in inhibition of lipopolysacch aride-stimulated cytokine production. Furthermore, anti-TGF-beta antib ody, indomethacin, or PAF receptor antagonists restored cytokine produ ction in lipopolysaccharide-stimulated macrophages that had phagocytos ed apoptotic cells, These results suggest that binding and/or phagocyt osis of apoptotic cells induces active antiinflammatory or suppressive properties in human macrophages. Therefore, it is likely that resolut ion of inflammation depends not only on the removal of apoptotic cells but on active suppression of inflammatory mediator production, Disord ers in either could result in chronic inflammatory diseases.