Regulation of neutrophils in ulcerative colitis by colonic factors: a possible mechanism of neutrophil activation and tissue damage.
The mucosal injury of active ulcerative colitis (UC) could involve enhanced migration and activation of neutrophils (PMNs). Because, in vitro, PMNs from patients with UC appear normal and are not therefore a likely cause for the enhancements, we hypothesized an abnormal colonic milieu. We previously found that factors in the UC colonic milieu markedly increase production of reactive oxygen species (ROS) by control PMNs. We now hypothesize that these factors also regulate PMN surface integrins, that regulation of UC PMNs is different than that of control PMNs, and that the integrin regulation is consistent with the ROS regulation. Using rectal dialysis, we sampled the colonic milieu in patients with active UC, in patients with inactive UC, and in control subjects. We monitored a key PMN adhesion molecule, CD11b. When control PMNs were tested, active UC rectal dialysate was almost as effective (+115%) as N-formyl-methionyl-leucyl-phenylalanine (+132%) in up-regulating CD11b. When inactive UC PMNs were tested, baseline CD11b was 50% higher than that for control PMNs. In contrast, rectal dialysates failed to up-regulate CD11b of inactive UC PMNs and in fact down-regulated CD11b. Preincubating control PMNs with UC rectal dialysates converted their CD11b response to PMN activators from up-regulation to down-regulation, mimicking inactive UC PMNs. Changes in intracellular calcium levels paralleled these changes in CD11b. Rectal dialysate-induced changes in both CD11b and calcium paralleled our previous findings on rectal dialysate-induced changes in ROS production. Thus the net overall effect of factors in the colonic milieu is a consistent and predictable regulation of PMN function--proinflammatory in UC, anti-inflammatory in control subjects. These factors may be a critical part of the pathophysiology of UC.
Robinson
C E
CE
Department of Medicine, Loyola University Stritch School of Medicine, Maywood, IL 60153, USA.
Kottapalli
V
V
D'Astice
M
M
Fields
J Z
JZ
Winship
D
D
Keshavarzian
A
A
D000328:Adult; D002118:Calcium / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000276:immunology*; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016177:Macrophage-1 Antigen / Q000032:analysis; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D018375:Neutrophil Activation; D009504:Neutrophils / Q000276:immunology*
D016177:Macrophage-1 Antigen; D009240:N-Formylmethionine Leucyl-Phenylalanine; D002118:Calcium