Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease.
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 (111)In-labeled neutrophils at these sites and clearance of (32)P-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.
Smith
Andrew M
AM
Department of Medicine, University College London, London WC1E 6BT, England, UK.
Rahman
Farooq Z
FZ
Hayee
Bu'Hussain
B
Graham
Simon J
SJ
Marks
Daniel J B
DJ
Sewell
Gavin W
GW
Palmer
Christine D
CD
Wilde
Jonathan
J
Foxwell
Brian M J
BM
Gloger
Israel S
IS
Sweeting
Trevor
T
Marsh
Mark
M
Walker
Ann P
AP
Bloom
Stuart L
SL
Segal
Anthony W
AW
D000328:Adult; D000368:Aged; D003424:Crohn Disease / Q000276:immunology* / Q000382:microbiology; D016207:Cytokines / Q000378:metabolism*; D004926:Escherichia coli / Q000276:immunology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007205:Indium Radioisotopes; D016014:Linear Models; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000382:microbiology; D020411:Oligonucleotide Array Sequence Analysis; D010761:Phosphorus Radioisotopes; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; D007205:Indium Radioisotopes; D010761:Phosphorus Radioisotopes; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha