Delayed resolution of acute inflammation in ulcerative colitis is associated with elevated cytokine release downstream of TLR4.
BACKGROUND
Ulcerative colitis (UC) is widely viewed as a leukocyte-mediated disorder. Although strong evidence implicates an exuberant response to microbial components in its pathogenesis, no intrinsic immune defect has been identified and the underlying pathogenic mechanisms remain obscure.


RESULTS
The acute immune response to bacterial injection was determined in UC patients with quiescent disease and directly compared to healthy control subjects. Monocyte-derived macrophages were used to investigate bacterial recognition mechanisms in vitro. An exuberant and protracted acute inflammatory response to bacteria was evident in patients with UC, which coincides with increased systemic levels of CXCL10. Macrophages stimulated with bacteria and Toll-like receptor (TLR) ligands revealed a specific defect in the TLR4 response in UC. The defect resulted in the over-expression of a number of pro-inflammatory molecules under transcriptional control of the adaptor TIR-domain containing adaptor inducing interferon-beta (TRIF).


CONCLUSIONS
These findings highlight a dysregulated innate immune response with over-expression of molecules associated with leukocyte recruitment and activation that may eventuate in the hallmark chronic immune-mediated inflammation of UC.
Rahman
Farooq Z
FZ
Departments of Medicine, University College London, London, United Kingdom.
Smith
Andrew M
AM
Hayee
Bu'Hussain
B
Marks
Daniel J B
DJ
Bloom
Stuart L
SL
Segal
Anthony W
AW
D003093:Colitis, Ulcerative / Q000473:pathology*; D016207:Cytokines / Q000096:biosynthesis*; D004926:Escherichia coli / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D016899:Interferon-beta / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis*; D051193:Toll-Like Receptors / Q000378:metabolism; D014158:Transcription, Genetic; D016896:Treatment Outcome
D016207:Cytokines; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D016899:Interferon-beta