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A correction to this article has been published: Smith et al., J. Exp. Med. 206 (10) 2301
Published online
doi:10.1084/jem.20091233
The Journal of Experimental Medicine, Vol. 206, No. 9, 1883-1897
The Rockefeller University Press, 0022-1007 $30.00
© Smith et al.
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ARTICLE

 Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease

Andrew M. Smith1, Farooq Z. Rahman1, Bu'Hussain Hayee1, Simon J. Graham4, Daniel J.B. Marks1, Gavin W. Sewell1, Christine D. Palmer1, Jonathan Wilde4, Brian M.J. Foxwell5, Israel S. Gloger4, Trevor Sweeting2, Mark Marsh3, Ann P. Walker1, Stuart L. Bloom6, and Anthony W. Segal1

1 Department of Medicine, 2 Department of Statistical Science, and 3 Medical Research Council Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, England, UK
4 Molecular and Cellular Technologies, Molecular Discovery Research, GSK, Harlow, Essex CM19 5AW, England, UK
5 Kennedy Institute of Rheumatology, Imperial College London, London W6 8LH, England, UK
6 Department of Gastroenterology, University College London Hospital, London NW1 2BU, England UK

CORRESPONDENCE Anthony W. Segal: t.segal{at}ucl.ac.uk

The cause of Crohn's disease (CD) remains poorly understood. Counterintuitively, these patients possess an impaired acute inflammatory response, which could result in delayed clearance of bacteria penetrating the lining of the bowel and predispose to granuloma formation and chronicity. We tested this hypothesis in human subjects by monitoring responses to killed Escherichia coli injected subcutaneously into the forearm. Accumulation of 111In-labeled neutrophils at these sites and clearance of 32P-labeled bacteria from them were markedly impaired in CD. Locally increased blood flow and bacterial clearance were dependent on the numbers of bacteria injected. Secretion of proinflammatory cytokines by CD macrophages was grossly impaired in response to E. coli or specific Toll-like receptor agonists. Despite normal levels and stability of cytokine messenger RNA, intracellular levels of tumor necrosis factor (TNF) were abnormally low in CD macrophages. Coupled with reduced secretion, these findings indicate accelerated intracellular breakdown. Differential transcription profiles identified disease-specific genes, notably including those encoding proteins involved in vesicle trafficking. Intracellular destruction of TNF was decreased by inhibitors of lysosomal function. Together, our findings suggest that in CD macrophages, an abnormal proportion of cytokines are routed to lysosomes and degraded rather than being released through the normal secretory pathway.

Dr. Foxwell died on 17 December 2008

A.M. Smith and F.Z. Rahman contributed equally to this paper.

Abbreviations used: Bref-A, brefeldin A; CD, Crohn's disease; cDNA, complementary DNA; DSS, dextran sodium sulfate; FDR, false discovery rate; GWAS, genome-wide association studies; HC, healthy control; HkEc, heat-killed E. coli; mRNA, messenger RNA; UC, ulcerative colitis.

© 2009 Smith et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease
Andrew M. Smith, Farooq Z. Rahman, Bu'Hussain Hayee, Simon J. Graham, Daniel J.B. Marks, Gavin W. Sewell, Christine D. Palmer, Jonathan Wilde, Brian M.J. Foxwell, Israel S. Gloger, Trevor Sweeting, Mark Marsh, Ann P. Walker, Stuart L. Bloom, and Anthony W. Segal
J. Exp. Med. 2009 206: 2301. [Full Text] [PDF]



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