Imbalance of the interleukin 1 system in colonic mucosa--association with intestinal inflammation and interleukin 1 receptor antagonist [corrected] genotype 2

Abstract

Background: Interleukin 1 (IL-1) alpha and beta are potent cytokines which play key roles in inflammation. They are controlled by IL-1 receptor antagonist (IL-1ra).

Aims: To investigate the influence of mucosal inflammation and IL-1ra genotype on the IL-1ra:IL-1 balance.

Patients and methods: IL-1 alpha, IL-1 beta, and IL-1ra were measured by enzyme linked immunosorbent assay (ELISA) in biopsy specimens taken from inflamed and non-inflamed colon of 60 patients with Crohn's disease (CD), 34 with ulcerative colitis (UC), 15 inflammatory controls, and 103 non-inflamed controls. IL-1ra genotype was determined by polymerase chain reaction and gel electrophoresis.

Results: IL-1 alpha and IL-1 beta were significantly increased in inflamed mucosa in inflammatory bowel disease (IBD) (CD: 53.5 (22.4) and 409.9 (118.7) pg/mg protein, respectively; UC: 18.9 (6.8) and 214.5 (78.2) pg/mg, respectively) and non-IBD patients (19.2 (7.4) and 281.4 (121.0) pg/mg, respectively; p < 0.0001) compared with normal controls (2.8 (0.6) and 30.6 (5.6) pg/mg, respectively). In CD IL-1 alpha and beta were also significantly increased in non-inflamed mucosa (6.1 (1.3) pg/mg and 88.7 (17.4) pg/mg, respectively; p < 0.0012). IL-1ra:(IL-1 alpha+beta) ratios were significantly decreased in inflamed mucosa of patients with CD (182 (45); p < 0.0001), UC (425 (136); p = 0.0018) and without IBD (221 (76); p < 0.0001), and in non-inflamed mucosa in CD (369 (149); p < 0.0001) compared with normal controls (1307 (245); p < 0.0001). Patients with IL-1ra genotype 2 had slightly but significantly reduced mucosal IL-1ra concentrations (p = 0.003). The greatest difference was seen in colonic biopsy specimens from patients with inflamed Crohn's disease.

Conclusion: Mucosal inflammation can modulate the balance of the IL-1:IL-1ra system in colonic mucosa.

Figure 1

: Different IL-1ra genotypes. The following genotypes are shown (from left to right) 1/3, 2/2, 1/1, 1/2, 1/2. A λ Pst l digest was used as size standard.

Figure 2

: IL-1α (A), IL-1β (B), IL-1ra (C), and IL-1ra:IL-1α+β ratios (D) in colonic mucosa. Data were logarithmically transformed (to achieve a normal distribution) and were expressed as means (95% confidence intervals). Asterisks indicate statistically significant differences compared with non-inflamed controls.

Figure 3

: Intraindividual concentrations of IL-1α (A), IL-1β (B), IL-1ra (C), and IL-1ra:IL-1α+β ratios (D) in inflamed and non-inflamed colonic mucosa of patients with CD. Data were logarithmically transformed (to achieve a normal distribution) and were expressed as means (95% confidence intervals). Asterisks indicate statistically significant differences between inflamed and non-inflamed regions.

Figure 4

: IL-1ra in colonic mucosa and genetic polymorphism of IL-1ra. Data were logarithmically transformed (to obtain a normal distribution) and are expressed as mean (SEM).

Figure 5

: Genetic polymorphism of IL-1ra and mucosal concentrations of IL-1α, IL-1β, and IL-1ra. IL-1(α+β) (A), and IL-1ra (B) were determined and ratios of IL-1ra:IL-1α+β were calculated (C). In order to combine the data of different groups the influence of diagnosis and inflammation was excluded by Z normalisation. The Z normalised values of the data are given as mean (95% confidence interval) and grouped by the number of IL-1ra genotype 2 alleles. The asterisk indicates a statistically significant difference compared with the patients with no IL-1ra allele.