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Am J Physiol Cell Physiol 295: C2-C12, 2008. First published April 23, 2008; doi:10.1152/ajpcell.00572.2007
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PROTEIN AND VESICLE TRAFFICKING, CYTOSKELETON

Hypoxia enhances lysosomal TNF-{alpha} degradation in mouse peritoneal macrophages

Nitza Lahat,1,* Michal A. Rahat,1,* Amalia Kinarty,1 Lea Weiss-Cerem,2 Sigalit Pinchevski,1 and Haim Bitterman2

1Immunology Research Unit and 2Ischemia-shock Research Laboratory, Carmel Medical Center, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

Submitted 3 December 2007 ; accepted in final form 21 April 2008

Infection, simulated by lipopolysaccharide (LPS), is a potent stimulator of tumor necrosis factor-{alpha} (TNF-{alpha}) production, and hypoxia often synergizes with LPS to induce higher levels of the secreted cytokine. However, we show that in primary mouse peritoneal macrophages and in three mouse peritoneal macrophage cell lines (RAW 264.7, J774A.1, and PMJ-2R), hypoxia (O2 < 0.3%) reduces the secretion of LPS-induced TNF-{alpha} (P < 0.01). In RAW 264.7 cells this reduction was not regulated transcriptionally as TNF-{alpha} mRNA levels remained unchanged. Rather, hypoxia and LPS reduced the intracellular levels of TNF-{alpha} by twofold (P < 0.01) by enhancing its degradation in the lysosomes and inhibiting its secretion via secretory lysosomes, as shown by confocal microscopy and verified by the use of the lysosome inhibitor Bafilomycin A1. In addition, although hypoxia did not change the accumulation of the soluble receptor TNF-RII, it increased its binding to the secreted TNF-{alpha} by twofold (P < 0.05). We suggest that these two posttranslational regulatory checkpoints coexist in hypoxia and may partially explain the reduced secretion and diminished biological activity of TNF-{alpha} in hypoxic peritoneal macrophages.

cytokines; inflammation; trafficking; secretory lysosomes


Address for reprint requests and other correspondence: M. A. Rahat, Immunology Research Unit, Carmel Medical Center, 7 Michal St., Haifa, 34362 Israel (e-mail: rahat_miki{at}clalit.org.il)






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