Activation of neutrophil Chemotaxis by leukotriene B4 and 5-hydroxyeicosatetraenoic acid in chronic inflammatory bowel disease

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Abstract
Circulating neutrophils were investigated in 15 patients with Crohn's disease (CD), 15 with ulcerative colitis (UC), and 15 healthy volunteers. Dose-response curves for Chemotaxis in Boyden chambers were analysed for sensitivity to leukotriene B4 (LTB4), its 20-hydroxy-LTB4 (20-OH-LTB4) and 20-carboxy-LTB4 (20-COOH-LTB4) catabolites, and 5- and 15-hydroxyeicosatetraenoic acids (HETEs). Positive controls included: complement 5a (C5a), formy-L-methionyl-L-leucyl-L-phenylalanine (f-Met-Leu-Phe), and casein. Control Chemotaxis test were performed at concentrations yielding optimal responses in leucocytes of healthy volunteers. Chemotaxis to suboptimal concentrations of LTB4 1.0 and 3.2 nmol/l, and 5-HETE 316 nmol/l, was markedly depressed in patients with chronic inflammatory bowel disease (CIBD). Analyses of individual dose-response curves revealed an underlying decreased sensitivity to LTB4 in 11 out of 30 patients, to 5-HETE in 10 out of 30 patients with a corresponding decrease of median sensitivity to LTB4 and 5-HETE in both CD and UC. Peak responses to LTB4, 5-HETE, f-Met-Leu-Phe, and casein were identical in the three groups tested, whereas the C5a values were significantly depressed in both groups of patients (p4 exceeded that of 5-HETE by a factor of approximately 100 whereas 20-OH-LTB4 was nearly as potent as LTB4. 20-COOH-LTB4 and 15-HETE did not activate Chemotaxis of human neutrophils. These findings are suggestive of a competitive inhibition of receptors with heterogeneity for LTB4 and 5-HETE. The depressed sensitivity of peripheral neutrophils to the potent lipoxygenase metabolites of arachidonic acid, LTB4 and 5-HETE, in CIBD may tend to limit their inflammatory recruitment in analogy with previous findings concerning Chemotaxis to C5a.

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