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TNF-alpha inhibits macrophage clearance of apoptotic cells via cytosolic phospholipase A(2) and oxidant-dependent mechanisms

Title
TNF-alpha inhibits macrophage clearance of apoptotic cells via cytosolic phospholipase A(2) and oxidant-dependent mechanisms
Authors
McPhillips, KathleenJanssen, William J.Ghosh, MoumitaByrne, AideenGardai, ShyraRemigio, LindaBratton, Donna L.Kang, Jihee L.Henson, Peter
Ewha Authors
이지희
SCOPUS Author ID
이지희scopus
Issue Date
2007
Journal Title
JOURNAL OF IMMUNOLOGY
ISSN
0022-1767JCR Link
Citation
vol. 178, no. 12, pp. 8117 - 8126
Publisher
AMER ASSOC IMMUNOLOGISTS
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Removal of apoptotic cells from inflammatory sites is an important step in the resolution of inflammation. Both murine and human macrophages stimulated with TNF-alpha or directly administered arachidonic acid showed an impaired ability to ingest apoptotic cells (efferocytosis). The inhibition was shown to be due to generation of reactive oxygen species, was blocked with a superoxide dismutase mimetic, MnTBAP, and was mimicked by direct addition of H2O2. To determine the mechanism of TNF-alpha-stimulated oxidant production, bone marrow-derived macrophages from gp91(phos)-deficient mice were examined but shown to still produce oxidants and exhibit defective apoptotic cell uptake. In contrast, a specific cytosolic phospholipase A(2) inhibitor blocked the oxidant production and reversed the inhibited uptake. The suppressive effect of endogenous or exogenous oxidants on efferocytosis was mediated through activation of the GTPase, Rho. It was reversed in macrophages pretreated with C3 transferase to inactivate Rho or with an inhibitor of Rho kinase. During maturation of human monocyte-derived macrophages, only mature cells exhibited TNF-alpha-induced suppression of apoptotic cell clearance. The resistance of immature macrophages to such inhibition was shown to result not from defective generation of oxidants, but rather, from lack of response of these cells to the oxidants. Overall, the data suggest that macrophages in a TNF-alpha- and oxidant-rich inflammatory environment are less able to remove apoptotic cells and, thereby, may contribute to the local intensity of the inflammatory response.
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의학전문대학원 > 의학과 > Journal papers
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