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This article is part of the supplement: Proceedings of the 8th Global Arthritis Research Network (GARN) Meeting and 1st Bio-Rheumatology International Congress (BRIC)

Poster presentation

Conditional inactivation of the ectodomain shedding of pro-TNFα in monocytes prevents lethality from LPS-induced septic shock

Keisuke Horiuchi1*, Tokuhiro Kimura2, Yasunori Okada2, Kazuhiro Chiba1, Carl P Blobel3 and Yoshiaki Toyama1

  • * Corresponding author: Keisuke Horiuchi

Author Affiliations

1 Department of Orthopedic Surgery, School of Medicine, Keio Univ. Tokyo, Japan

2 Department of Pathology, School of Medicine, Keio Univ. Tokyo, Japan

3 Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, USA

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Arthritis Research & Therapy 2012, 14(Suppl 1):P25  doi:10.1186/ar3626


The electronic version of this article is the complete one and can be found online at: http://arthritis-research.com/content/14/S1/P25


Published:9 February 2012

© 2012 Horiuchi et al.; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background

TNFα is synthesized as a membrane-bound precursor and proteolytically released from cells. Soluble TNFα is the primary mediator of pathologies such as rheumatoid arthritis, Crohn's disease, and endotoxin shock. Although several different enzymes have been implicated in this proteolytic activity, recent studies lean toward the TNFα converting enzyme (TACE/ADAM17) as the most relevant TNFαsheddase in vivo. In the present study, we asked whether the inactivation TACE could yield a protection from lipopolysaccharide(LPS)-induced septic shockin mice.

Materials and methods

To abrogate TNFα shedding activity in vivo, we generated conditional TACE-deficient mice using Cre-loxP system [1]. We mated these mice with Mx1-Cretg mice and LysM-Cretg mice to inactivate TACE in BM cells and macrophage/monocyte lineage cells, respectively. Endotoxin shock was induced by i.p. injection of 5 μg of LPS and 20 mg of D-galactosamine. All injected mice were closely monitored every hour for the first 16 h and every 3-6 h thereafter.

Results/conclusions

We found that temporal disruption of TACE under the control of Mx1 transgene prevented lethality from endotoxin shock. Furthermore, inactivation of TACE in macrophage/monocyte lineage cells also rendered significant protection against LPS-induced septic shock. Consistent with these findings, serum TNFα levels in the TACE mutant mice were much lower than those in control mice. The present study thus shows that 1) TACE is indeed a principal enzyme responsible for the release of soluble TNFα in vivo, and that 2) inactivation of TACE in macrophage/monocyte lineage cells is sufficient to yield strong protection against LPS-induced endotoxin shock. Taken together, the present data indicate inhibition of TACE activity as a potential therapeutic target for TNFα-related disorders.

References

  1. Horiuchi K, Kimura T, Miyamoto T, et al.: TNF-α-converting enzyme (TACE/ADAM17) inactivation in mouse myeloid cells prevents lethality from endotoxin shock.

    J Immunol 2007, 179:2686-2689. PubMed Abstract | Publisher Full Text OpenURL