Efficacy of recombinant granulocyte colony-stimulating factor (rhG-CSF) in experimental colitis

Abstract

SUMMARYInflammatory bowel disease is associated with mucosal neutrophil recruitment and activatation, mediated in part by arachidonic acid metabolites. G-CSF attenuates the immune response to sepsis and ameliorates glycogen storage disease Ib-related colitis. These actions may be effected through the shedding of neutrophil adhesion molecules, or inhibition of proinflammatory mediator synthesis. Immune complex colitis was used to evaluate the effect of rhG-CSF on colonic mucosal inflammation, neutrophil recruitment and the generation of eicosanoids. Immune complex colitis was induced in White New Zealand rabbits. Animals were pretreated with rhG-CSF either 24 h before induction, or at induction, with dosages of 50 and 200 g/kg. rhG-CSF caused a time-and dose-dependent neutrophilia in all animals. Pretreatment with rhG-CSF resulted in increased tissue myeloperoxidase levels, despite a histologically similar mucosal polymorphonuclear cell infiltrate between treated and control colitis groups. Leukotriene B 4 (LTB 4 ) and thromboxane B 2 (TXB 2 ) dialysis fluid levels were lower in treated animals, in particular in the groups receiving two doses (LTB 4 : both P < 0 : 01; TXB 2 : both P < 0 : 01. Prostaglandin E 2 (PGE 2 ) levels in dialysis fluid of the rhG-CSF-treated animals showed no difference from controls. In this model of experimental colitis, high-dose therapy with G-CSF resulted in a marked decrease of proinflammatory mediators, but mucosal generation of the protective PGE 2 was preserved. These results suggest that prolonged high-dose therapy with G-CSF may have anti-inflammatory effects in colitis.

Granulocyte Colony-Stimulating Factor: A Novel Mediator of T Cell Tolerance

“…Cytokine administration at either dose translated into increased tissue myeloperoxidase levels, despite a histologically similar mucosal polymorphonuclear cell infiltrate in the G-CSF-treated compared with the control colitis group. Moreover, dialysis fluid levels of leukotriene B4 and thromboxane B2 were significantly lower in treated animals (65). Similar results were obtained in the 2,4,6-trinitrobenzene sulfonic acid colitis in rats, a model of Th1 disease.…”

“…G-CSF has been successfully used in experimental colitis in White New Zealand rabbits (65). Animals were pretreated either 24 h before or at colitis induction either with 50 or 200 g/kg rG-CSF.…”

Depletion of endothelial progenitor cells in the peripheral blood of patients with ulcerative colitis

“…Dieckgraefe et al showed that the administration of GM-CSF, a potent stimulant for hematopoiesis, was effective for treating patients with active CD (38). These results in humans were supported by the results of animal studies demonstrating that bone marrow cells (39,40) or their inducers (41,42) could ameliorate experimental colitis.…”

Reduced expression of basal and probiotic-inducible G-CSF in intestinal mononuclear cells is associated with inflammatory bowel disease

“…In fact, administration of G-CSF has been shown to ameliorate colonic inflammation in animal models of colitis, 28,27 and be a safe and effective biologic agent for the treatment of active CD. 29 In this study, we have shown that G-CSF was highly expressed in noninflamed regions of both mouse and human intestinal lamina propria.…”

“…These effects include the suppression of proinflammatory cytokine production, 20 -23 and promotion of the generation of regulatory antigen presenting cells, 24 regulatory T (Treg) cells, 25 and Th2 cells. 22,26 Studies have also shown that G-CSF treatment is effective in ameliorating bowel inflammation in animal colitis models 27,28 and preclinical trials. 29,30 Although the immunomodulatory roles of G-CSF have been demonstrated, its role in maintaining immunological homeostasis in the intestine has not yet been addressed.…”