Differential normalization of mucosal interleukin-8 and interleukin-6 activity after Helicobacter pylori eradication

Abstract

There is differential resolution of mucosal infiltration with neutrophils and mononuclear cells following successful Helicobacter pylori eradication. We investigated the effects of H. pylori eradication on mucosal interleukin-8 (IL-8) and IL-6 activity in relation to the resolution of H. pylori-associated gastritis. Eighty-one duodenal ulcer patients with H. pylori infection received dual- or triple-treatment eradication therapy, and mucosal biopsy specimens obtained at the initial and follow-up endoscopic examinations were cultured in vitro for 24 h. The levels of IL-8 and IL-6 were measured by enzyme-linked immunosorbent assays. In the 42 patients in whom H. pylori eradication failed, there was little change in the numbers of neutrophils and mononuclear cells infiltrating the mucosa and in IL-8 and IL-6 activity. In the 39 patients in whom H. pylori was eradicated, there was normalization both in the numbers of infiltrating neutrophils and in mucosal IL-8 activity, which was evident within 1 month following therapy. In contrast, there was a gradual resolution of mononuclear cell infiltration over a 6-month period, accompanied by a gradual normalization in IL-6 levels. Addition of H. pylori to cultures of mucosal tissues induced a significant increase in IL-8 activity in both uninfected control subjects and patients from whom H. pylori was eradicated. However, this introduction yielded a significant increase in IL-6 activity only in the latter group. This study indicates a dichotomy in the changes of mucosal IL-8 and IL-6 activity after H. pylori eradication. The rapid normalization of IL-8 after H. pylori eradication and the ability of H. pylori cells to stimulate IL-8 in control tissues indicate that IL-8 induction is a part of the innate (nonimmune) responses to this organism. In contrast, the results of experiments analyzing IL-6 activity in cultured mucosal tissues suggest that the gradual resolution of mucosal IL-6 activity and mononuclear infiltration after successful eradication observed in vivo may reflect gradually diminishing residual immune responses against H. pylori.

FIG. 1

Histological analysis of activity defined by density of polymorphonuclear leukocytes (A), inflammation defined by density of mononuclear cells (B), and H. pylori density (C) in duodenal ulcer patients in whom H. pylori was or was not eradicated. Before, before treatment; 1M, 1 month after treatment; 6M, 6 months after treatment. ∗, P < 0.05 compared to value before treatment (χ² test).

FIG. 2

IL-8 (A) and IL-6 (B) levels in 24-h organ cultures of mucosal tissues in H. pylori-infected duodenal ulcer patients in whom eradication therapy was attempted and in uninfected controls. Data are stratified by whether eradication occurred (n = 39) or not (n = 42). Before, before treatment; 1M, 1 month after treatment; 6M, 6 months after treatment; 18M, 18 months after treatment. For the 18M group, samples were obtained from only 20 patients. Bars indicate median values for each group. In statistical analyses by paired t tests, all the following comparisons are significant (P < 0.05): for panel A, a versus b, a versus c, a versus d, e versus f, f versus i, g versus i, and h versus i; for panel B, a versus b, a versus c, b versus c, a versus d, b versus d, b versus i, f versus i, g versus i, and h versus i.

FIG. 3

Cytokine levels in 24-h organ cultures of mucosal tissues cocultured with a cagA-positive H. pylori strain ATCC 43504, or a cagA-negative strain, NUHP498. Tissues are from uninfected controls and from duodenal ulcer patients in whom H. pylori was eradicated. The specimens were obtained from the patients 6 months after eradication therapy. Bars indicate median values for each group. In statistical analyses by the Mann-Whitney U test, all the following comparisons are significant: for panel A, a versus c (P < 0.001), a versus e (P < 0.001), b versus d (P < 0.001), and b versus f (P < 0.001); for panel B, a versus c (P < 0.001) and a versus e (P < 0.001).