Colonic expression of leukotriene-pathway enzymes in inflammatory bowel diseases.
BACKGROUND
Leukotrienes derived from the 5-lipoxygenase pathway are proinflammatory lipid mediators that possibly play a role in inflammatory bowel diseases. The expression of 5-lipoxygenase pathway proteins has not previously been examined in colonic mucosa in inflammatory bowel disease.


RESULTS
Quantitative immunohistochemical analyses showed that, compared to those of the control subjects (n = 9), colonic biopsies from patients with active inflammatory bowel disease (n = 17) had 3- to 7-fold higher mean counts of cells expressing 5-lipoxygenase (P = 0.03), 5-lipoxygenase-activating protein (P = 0.005), and the leukotriene A(4) hydrolase (P = 0.004), which make up the biosynthetic pathway of the potent neutrophil chemotaxin leukotriene B(4). Immunoexpression of the leukotriene C(4) synthase was unaltered (P > 0.2). The increased representation of leukotriene B(4)-pathway enzymes was associated with higher counts of neutrophils (P = 0.0001), macrophages (P = 0.03), eosinophils (P = 0.0004), CD8(+) T cells (P < 0.001), activated T cells (P < 0.05), and B cells (P < 0.05) but not of mast cells (P > 0.9). These eicosanoid and cellular changes were most marked in the subgroup of patients with ulcerative colitis (n = 9), and were absent in patients with quiescent disease (n = 6). The anomalies in the 5-lipoxygenase pathway were accompanied as expected by more cells immunostaining for cytokine-inducible COX-2 (P = 0.004, n = 17), but this study also revealed a greater number of cells expressing COX-1 in the samples from the patients in the ulcerative colitis subgroup (P = 0.03, n = 9).


CONCLUSIONS
The 5-lipoxygenase data provide a cellular basis for increased tissue synthesis of the leukotriene B(4), as reflected in the colonic mucosa and rectal dialysates of patients with active inflammatory bowel disease, which contributes to neutrophil influx and colonic injury. The COX-1/COX-2 data highlight the ambiguous functional role of prostanoid pathways in inflammatory bowel diseases.
Jupp
James
J
Division of Infection, Inflammation & Repair, University of Southampton School of Medicine, Southampton General Hospital, Southampton, United Kingdom.
Hillier
Keith
K
Elliott
Daniel H
DH
Fine
David R
DR
Bateman
Adrian C
AC
Johnson
Penny A
PA
Cazaly
Angelica M
AM
Penrose
John F
JF
Sampson
Anthony P
AP
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D053898:Biosynthetic Pathways; D003106:Colon / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000378:metabolism; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D015212:Inflammatory Bowel Diseases / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D007413:Intestinal Mucosa / Q000201:enzymology / Q000378:metabolism*; D007962:Leukocytes / Q000473:pathology; D007975:Leukotriene B4 / Q000378:metabolism; D015289:Leukotrienes / Q000378:metabolism*; D008264:Macrophages / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000473:pathology; D008875:Middle Aged
D015289:Leukotrienes; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases; C041116:leukotriene-C4 synthase; C043134:leukotriene A4 hydrolase