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National Jewish Medical and Research Center, Denver, CO 80206
We recently reported that phagocytosis of apoptotic cells inhibits
the release of inflammatory cytokines by human macrophages. In this
paper we show that apoptotic cell uptake by mouse J774 macrophages also
inhibits the synthesis and secretion of the chemokines, macrophage
inflammatory protein-2 (Mip-2), KC, and Mip-1
(but not that of
monocyte chemoattractant protein-1 (MCP-1)/JE), and increases TGF-ß
formation. Anti-TGF-ß neutralizing Abs largely reversed the
inhibitory effect of apoptotic cell uptake, and accordingly, exogenous
TGF-ß down-regulated the synthesis of the same mediators. Apoptotic
cell ingestion or TGF-ß also inhibited Mip-2 and Mip-1 gene
expression in LPS-treated J774 cells, whereas TNF- mRNA levels were
unaffected. Importantly, TGF-ß pretreatment of J774 cells did not
significantly alter chemokine and TNF mRNA stability. Finally, we found
that apoptotic cell uptake and TGF-ß did not modulate NF-
B or AP-1
DNA binding in J774 cells. We conclude that the decreased production of
chemokines and TNF resulting from apoptotic cell ingestion is largely
mediated by a common event, i.e., feedback inhibition by endogenous
TGF-ß, but involves different mechanisms. Whereas TNF- production
appears to be translationally down-regulated, the suppression of most
chemokines investigated appears to reflect transcriptional inhibition.
In a broader context, the impairment of chemokine and TNF generation by
apoptotic cell uptake might represent an important mechanism
contributing to the resolution of inflammation. An additional
consequence could be the selective recruitment of monocytes into
inflammatory sites, as MCP-1/JE production by mouse macrophages was
unaffected by apoptotic cell uptake, in contrast to other
chemokines.
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B. Endlich, D. Armstrong, J. Brodsky, M. Novotny, and T. A. Hamilton Distinct Temporal Patterns of Macrophage-Inflammatory Protein-2 and KC Chemokine Gene Expression in Surgical Injury J. Immunol., April 1, 2002; 168(7): 3586 - 3594. [Abstract] [Full Text] [PDF]
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 C. A. Hetz, M. Hunn, P. Rojas, V. Torres, L. Leyton, and A. F. G. Quest Caspase-dependent initiation of apoptosis and necrosis by the Fas receptor in lymphoid cells: onset of necrosis is associated with delayed ceramide increase J. Cell Sci., January 12, 2002; 115(23): 4671 - 4683. [Abstract] [Full Text] [PDF]
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A. M. Hohlbaum, M. S. Gregory, S.-T. Ju, and A. Marshak-Rothstein Fas Ligand Engagement of Resident Peritoneal Macrophages In Vivo Induces Apoptosis and the Production of Neutrophil Chemotactic Factors J. Immunol., December 1, 2001; 167(11): 6217 - 6224. [Abstract] [Full Text] [PDF]
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P.L.E.M. van Lent, R. Licht, H. Dijkman, A.E.M. Holthuysen, J.H.M. Berden, and W.B. van den Berg Uptake of apoptotic leukocytes by synovial lining macrophages inhibits immune complex-mediated arthritis J. Leukoc. Biol., November 1, 2001; 70(5): 708 - 714. [Abstract] [Full Text] [PDF]
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T. Magnus, A. Chan, O. Grauer, K. V. Toyka, and R. Gold Microglial Phagocytosis of Apoptotic Inflammatory T Cells Leads to Down-Regulation of Microglial Immune Activation J. Immunol., November 1, 2001; 167(9): 5004 - 5010. [Abstract] [Full Text] [PDF]
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L. Tourneur, B. Malassagne, F. Batteux, M. Fabre, S. Mistou, E. Lallemand, P. Lores, and G. Chiocchia Transgenic Expression of CD95 Ligand on Thyroid Follicular Cells Confers Immune Privilege upon Thyroid Allografts J. Immunol., August 1, 2001; 167(3): 1338 - 1346. [Abstract] [Full Text] [PDF]
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M. Adib-Conquy, K. Asehnoune, P. Moine, and J.-M. Cavaillon Long-term-impaired expression of nuclear factor-{kappa}B and I{kappa}B{alpha} in peripheral blood mononuclear cells of trauma patients J. Leukoc. Biol., July 1, 2001; 70(1): 30 - 38. [Abstract] [Full Text] [PDF]
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 G. Wang, Y. L. Siow, and K. O Homocysteine induces monocyte chemoattractant protein-1 expression by activating NF-{kappa}B in THP-1 macrophages Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2840 - H2847. [Abstract] [Full Text] [PDF]
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V. A. Fadok, D. L. Bratton, L. Guthrie, and P. M. Henson Differential Effects of Apoptotic Versus Lysed Cells on Macrophage Production of Cytokines: Role of Proteases J. Immunol., June 1, 2001; 166(11): 6847 - 6854. [Abstract] [Full Text] [PDF]
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 R. E. Cocco and D. S. Ucker Distinct Modes of Macrophage Recognition for Apoptotic and Necrotic Cells Are Not Specified Exclusively by Phosphatidylserine Exposure Mol. Biol. Cell, April 1, 2001; 12(4): 919 - 930. [Abstract] [Full Text]
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D. Shiffman, T. Mikita, J. T. N. Tai, D. P. Wade, J. G. Porter, J. J. Seilhamer, R. Somogyi, S. Liang, and R. M. Lawn Large Scale Gene Expression Analysis of Cholesterol-loaded Macrophages J. Biol. Chem., November 22, 2000; 275(48): 37324 - 37332. [Abstract] [Full Text] [PDF]
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