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ORIGINAL RESEARCH ARTICLE

Redox State and O₂^•– Production in Neutrophils of Crohn’s Disease Patients

Chiara Biagioni^*, Fabio Favilli^*, Serena Catarzi^*, Tommaso Marcucci, Marilena Fazi, Francesco Tonelli, Maria T. Vincenzini^* and Teresa Iantomasi^*,1

^* Department of Biochemical Sciences, and General Surgery Unit, Department of Clinical Physiopathology, University of Florence, 50134 Florence, Italy

To whom requests for reprints should be addressed at ¹ Department of Biochemical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy. E-mail: tiantomasi{at}unifi.it

The aim of this in vitro study was to evaluate the intracellular redox state and respiratory burst (RB) in neutrophils of patients with Crohn’s disease (CD). The intracellular redox state and RB in neutrophils was assessed by the superoxide anion (O₂^•–) production induced in these cells after stimulation by various factors related to the molecular mechanisms that, if altered, may be responsible for an abnormal immune response. This can, in part, cause the onset of inflammation and tissue damage seen in CD. This study demonstrated a decreased glutathione/glutathione disulfide (GSH/GSSG) ratio index of an increased oxidative state in CD patient neutrophils. Moreover, our findings showed a decrease in tumor necrosis factor (TNF-)– or phorbol 12-myristate 13-acetate (PMA)–induced O₂^•– production in CD patient neutrophils adherent to fibronectin as compared with controls. A decreased adhesion was also demonstrated. For this reason, the involvement of altered mechanisms of protein kinase C (PKC) and ß-integrin activation in CD patient neutrophils is suggested. These data also showed that the harmful effects of TNF- cannot be caused by excessive reactive oxygen species (ROS) production induced by neutrophils. Decreased cell viability after a prolonged time of adhesion (20 hrs) was also measured in CD patient neutrophils. The findings of this study demonstrate, for the first time, that granulocyte-macrophage colony–stimulating factor (GM-CSF), a compound recently used in CD therapy, is able to activate the RB for a prolonged time both in control and CD patient neutrophils. Increased viability of CD patient neutrophils caused by GM-CSF stimulation was also observed. In conclusion, our results indicate that decreased O₂^•– production and adhesion, caused, in part, by an anomalous response to TNF-, together with low GSH level and low cell viability, may be responsible for the defective neutrophil function found in CD patients. This can contribute to the chronic inflammation and relapses that characterize this pathology. A possible role of GM-CSF in inducing O₂^•– production and in restoring the defensive role of neutrophils in CD patients is suggested.

Key Words: Crohn’s disease • GM-CSF • GSH • redox state • neutrophils O₂^•– production • TNF-

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