Increased mucosal production of granulocyte colony‐stimulating factor is related to a delay in neutrophil apoptosis in Inflammatory Bowel disease

Abstract

Tissue accumulation of polymorphonuclear neutrophils (PMN) in Inflammatory Bowel disease (IBD) might be, in part, due to a delay in apoptotic processes associated with the effects of their specific growth factors and inflammatory cytokines. We addressed this hypothesis by examining the activity of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF) in the organ culture supernatants of colonic mucosal specimens and their regulatory effects on PMN apoptosis in patients with IBD. The contents of G-CSF and GM-CSF in the supernatants were measured by the enzyme-linked immunosorbent assays and PMN apoptosis was evaluated by acridine orange/ethidium bromide staining, respectively. Mucosal specimens obtained from patients with active IBD exhibited higher levels of G-CSF and GM-CSF activity than controls. Notably, the levels of G-CSF activity were approximately 1000-fold higher than those of GM-CSF activity. Freshly isolated PMN showed a time-related increase in the proportion of cells with characteristic features of apoptosis when they were incubated with the culture medium alone and exposure of PMN to recombinant G-CSF and GM-CSF caused a concentration-dependent inhibition of apoptosis. Incubation of PMN with the supernatants from patients with active IBD induced an inhibitory effect on PMN apoptosis; this effect was abrogated to a significant degree by pre-incubation of the supernatants with anti-G-CSF serum. This study suggests that PMN apoptosis may be delayed under the influence of soluble mediators, especially G-CSF, in the microenvironment of IBD-affected mucosa, thus providing possible mechanisms for tissue accumulation of PMN in IBD.

Bromelain treatment decreases secretion of pro-inflammatory cytokines and chemokines by colon biopsies in vitro

“…These cytokines have previously been shown to be increased in media derived from organ cultures of colon tissues from patients with active IBD (23)(24)(25). This provides an additional validation of the use of organ culture methods used here to study the effects of experimental bromelain treatment on cytokine secretion.…”

“…G-CSF has previously been noted to be increased in organ culture supernatants of colon tissues from patients with IBD (24). G-CSF was demonstrated to delay apoptosis of neutrophils, an activity that could lead to accumulation of neutrophils in mucosal tissues of IBD patients (25). However, CD has also been associated with neutropenia and with impaired neutrophil migration.…”

Tumor-Derived GM-CSF Promotes Inflammatory Colon Carcinogenesis via Stimulating Epithelial Release of VEGF

“…Granulocyte macrophage colony-stimulating factor (GM-CSF) is a hematopoietic cytokine, whose levels are significantly elevated in the inflamed tissues of patients with IBD and rodents subjected to experimental colitis (10,11). In accordance with this, GM-CSF À/À mice were more susceptible to DSS-induced colitis, as shown by clinical and histologic parameter and by augmented proinflammatory cytokine production (12).…”

Constitutive neutrophil apoptosis: Mechanisms and regulation

“…Because lung and liver damage can be attenuated by antineutrophil treatment, delayed neutrophil death might contribute to the organ damage SIRS [127][128][129]. In addition, a variety of autoimmune/rheumatic diseases such as crystalline arthritis [130,131], inflammatory bowel disease [132], and rheumatoid arthritis [133,134] are associated with the decreased propensity of neutrophils, leading towards apoptosis.…”