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J. Biol. Chem., Vol. 278, Issue 23, 20555-20564, June 6, 2003

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TLR4-dependent Lipopolysaccharide-induced Shedding of Tumor Necrosis Factor Receptors in Mouse Bone Marrow Granulocytes^*

Thierry Pedron , Robert Girard  and Richard Chaby ¶ ||

From the Unité de Pathogénie Microbienne Moléculaire, Unité INSERM U389, Institut Pasteur, 75015 Paris, Lymphocyte Development, URA-1961 of the National Center for Scientific Research, Pasteur Institute, 75015 Paris, and the ^¶Endotoxin Group, UMR-8619 of the National Center for Scientific Research, University of Paris-Sud, 91405 Orsay, France

We reported previously that bone marrow granulocytes respond to small amounts of enterobacterial lipopolysaccharide (LPS) via a CD14-independent and TLR4-mediated mechanism by de novo expression of an inducible receptor (CD14) and by down-modulation of a constitutive receptor (L-selectin). In this report we address another effect of LPS: the down-regulation of receptors for tumor necrosis factor-. In mouse bone marrow cells (BMC), this down-regulation is detectable soon (20 min) after exposure of the cells to low levels (0.5 ng/ml) of LPS. This temperature-dependent effect is rather selective for LPS and requires the presence of a conventional lipid A structure in the LPS molecule and a functional TLR4 molecule in the cells. The down-modulation, due to a shedding of the receptors, is blocked by p38 MAPK inhibitors, by a furin inhibitor, and by three metalloproteinase inhibitors (BB-3103, TIMP-2, and TIMP-3). In contrast, inhibitors of MEK, protein kinase C, cAMP-dependent protein kinase, and kinases of the Src family do not block the shedding. Analysis of BMC from mice lacking tumor necrosis factor receptor-1 (CD120a^–/–) or tumor necrosis factor receptor-2 (CD120b^–/–) indicates that the LPS-induced shedding is specific for CD120b. Thus, exposure of BMC to LPS triggers a rapid shedding of CD120b via a protein kinase C- and Src-independent pathway mediated by p38 MAPK, furin, and metalloproteinase. The additive effects of furin and metalloproteinase inhibitors suggest that these enzymes are involved in parallel shedding pathways.

Received for publication, April 12, 2002 , and in revised form, February 28, 2003.

^* This work was supported by Grants 5045 from the Pasteur Institute and 1961 from the CNRS. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed. Tel.: 33-169154830; Fax: 33-169853715; E-mail: richard.chaby{at}bbmpc.u-psud.fr.

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