Production and cellular source of interleukin-8 in ulcerative colitis

Abstract

: Evidence has accumulated that interleukin-1β (IL-1β) plays an pivotal role in mediating the inflammatory changes in ulcerative colitis (UC) and that interleukin-8 (IL-8) is responsible for some of the neutrophil-activating actions of IL-1β in vivo. We determined the IL-8 content and its cellular source in mucosal specimens of patients with UC, and analyzed whole gut lavage fluid on the presence of IL-8. In addition, we monitored these patients for a follow-up period of 1 year to see if IL-8 levels are indicative for colon at risk. Patients with active disease were enrolled; disease activity, endoscopical scores, and histopathological grading were assessed. Transcription and translation of IL-8 were demonstrated by in situ hybridisation and immunohistochemistry. Biopsy specimens from 30 UC patients and five controls were homogenized, and IL-8 content was determined. Lavage fluid from 10 UC patients and six controls was processed and analyzed for the presence of IL-8. Clinical events were monitored for a period of 1 year. IL-8 production was detected in both enterocytes and mucosal inflammatory cells. The mean IL-8 content in control biopsy specimens was 98.0 pg/mg (±10 pg/mg). The IL-8 content was 176.7 pg/mg (±21 pg/mg) in specimens obtained from noninflamed colon regions of UC patients, and 204 pg/mg (±27 pg/mg) in specimens taken from inflamed colonic areas (p = 0.023 and p = 0.013, respectively). The mean IL-8 levels in lavage fluid from UC patients was 36.4 pg/ml (±22.5 pg/ml) versus 3.1 pg/ml (±0.8 pg/ml) in control patients (p < 0.05). Lavage IL-8 levels correlated with endoscopical score (r = 0.81; p = 0.009). During a follow-up period of 1 year, patients with high IL-8 levels in their noninvolved colon mucosa experienced more flare-ups than patients with low levels of normal mucosal IL-8. This study demonstrates that IL-8 is expressed in the normal large bowel mucosa. High levels are present in both macroscopically inflamed and noninflamed mucosa in UC. Both enterocytes and inflammatory cells contribute to the IL-8 production. Analysis of gut perfusate can be used to study IL-8 in UC, and IL-8 production in normally appearing mucosa in patients with ulcerative colitis may be indicative of colon at risk for inflammation.

Increased expression of interleukin-8 mRNA in ulcerative colitis and Crohn's disease mucosa and epithelial cells

“…Neutrophils not only play a major role in defense against bacterial infection, but also up-regulate and increase mucosal immune defensive capabilities by producing oxygen radicals, PAF, LTB,, IL-lp, as well as 37). These normally protective functions may be up-regulated and perpetuated in IBD, leading to tissue damage by many of the same molecules (18)(19)(20)(21)(26)(27)(28)32,(38)(39)(40)(41)(42). Depletion of neutrophils by monoclonal antibodies also leads to inhibition of the subsequent IL-8-induced in vivo migration of CD4+ T cell subsets (43) and inhibits alterations in vascular permeability induced by IL-Ip and TNF-a (44).…”

A Central Role for Heme Oxygenase-1 in the Control of Intestinal Epithelial Chemokine Expression

“…The findings of HO-1 regulation of IL-8 secreted by IECs is particularly important given prior evidence that IECs and intestinal mast cells are the main source of basal intestinal IL-8 secretion [9]. Such basal secretion is responsible for the recruitment and protective retention of intestinal macrophages, but in excess, can contribute to IBD pathogenesis [11]. We propose that in this setting, HO-1 sub-serves the mucosal inflammatory response by functioning as an endogenous braking mechanism to uncontrolled chemokine production.…”