Removal of these Everolimus nmr cells occurs rapidly and without induction of a proinflammatory milieu 1. In recent years, it has become apparent that the removal of apoptotic cells by macrophages and DC is not only noninflammatory but also immune-inhibitory 2–8, in most although not all circumstances. Fadok et al. 2 showed that efferocytosis (clearance of apoptotic cells, a terminology suggested by the Henson group) inhibited the production of proinflammatory
cytokines such as IL-8 and IL-1β, and induced the secretion of TGF-β, platelet-activating factor, and prostaglandin E2. They further showed and suggested that these factors inhibited a proinflammatory response to LPS and zymosan, by autocrine or paracrine mechanisms, via the secreted factors. Later, Huynh et al. 4 showed that the resolution of acute inflammation selleck screening library is dependent on phosphatidylserine expressed by apoptotic cells, and on TGF-β, secreted most probably by macrophages following engulfment of apoptotic cells expressing phosphatidylserine. Freire-de-Lima et al. 3 further showed
that through TGF-β, apoptotic cells simultaneously induce an anti-inflammatory milieu and suppress proinflammatory eicosanoid and NO synthesis in murine macrophages. Hence, the proposed model for inhibition of a proinflammatory response to LPS and zymosan, as well as the resolution of acute inflammation, is based on ligation of phosphatidylserine expressed on apoptotic Levetiracetam cells to the presumed phosphatidylserine receptor, and possibly other receptors. This ligation is expected to result in immediate preformed TGF-β secretion from macrophages, followed by de novo synthesis of TGF-β. Additional mechanisms of inflammatory response inhibition in humans have been proposed by other groups (reviewed by Serhan and Savill,
9). We have recently shown that thrombospondin-1 ligation to phagocytic cells 5 and STAT-1 inhibition 7 are additional inhibitory mechanisms. In some circumstances, clearance of apoptotic cells and necrotic cells can be proinflammatory, as a result, for example, of autoantibody-opsonization of apoptotic cells or release of proinflammatory molecules such as high mobility group box-1 protein (HMGB1) 10. We and others were also able to show that complement may be involved in apoptotic cell uptake via direct binding of bridging factors like C1q and mannose-binding lectin 11, or formation of iC3b on the surface of apoptotic cells 8, 12, 13. Thus, opsonization by complement and engagement of the complement receptors CD11b/CD18 and CD11c/CD18 may suggest an alternative or complementary clearance mechanism. Complement opsonization of bacteria was generally known for its proinflammatory effects.