Profile of soluble cytokine receptors in Crohn's disease

Abstract

Introduction: Soluble cytokine receptors (sCRs) modulate the in vivo activity of cytokines. Deficient sCR production could participate in the pathogenesis and course of Crohn's disease (CD). The aim of the study was to examine the profile of sCRs in CD patients and their modulation by infliximab and corticosteroids.

Methods: We prospectively examined active CD patients (aCD) treated with either infliximab (n = 21) or corticosteroids (n = 9), CD patients in clinical remission (rCD, n = 20), ulcerative colitis patients (UC, n = 24), and healthy subjects (HS, n = 15). Cultures of colonic biopsies were also examined from CD inflamed (n = 8), CD non-inflamed (n = 7), and healthy mucosa (n = 8). Levels of tumour necrosis factor alpha (TNF-alpha), soluble TNF receptor I (sTNFRI), soluble TNF receptor II (sTNFRII), interleukin 1beta (IL-1beta), soluble IL-1 receptor I (sIL-1RI), soluble IL-1 receptor II (sIL-1RII), IL-6, soluble IL-6 receptor (sIL-6R), and sgp130 were measured using ELISA.

Results: Higher levels of sTNFRI (p<0.05, p<0.01), sTNFRII (p<0.01, p<0.01), sIL-1RI (p<0.05, NS), IL-6 (p<0.01, p<0.01), and sIL-6R (p<0.05, NS) were observed in aCD compared with rCD and HS. Interestingly, sIL-1RII (p<0.05, p<0.01) and sgp130 (p<0.01, p<0.01) were profoundly decreased in aCD compared with rCD and HS, and were negatively correlated with CRP. Deficient production of sIL-1RII was specific to CD (not observed in ulcerative colitis), and was further confirmed at the mucosal level. Infliximab decreased sTNFRII at one and four weeks (p<0.05) and enhanced sIL-6R levels at one week (p<0.05). Corticosteroids increased sIL-1RII levels at one week (p<0.05).

Conclusion: CD is associated with dysregulated production of sCRs. Deficiency in sIL-1RII and sgp130 may be essential to CD pathogenesis. Their replacement through the use of fusion proteins could represent future alternative therapeutic strategies for CD.

Figure 1

Circulating soluble cytokine receptor levels in 15 healthy subjects (HS), 20 patients in Crohn’s disease remission (rCD), and 30 active Crohn’s disease patients (aCD). (A) Soluble tumour necrosis factor receptor I (sTNFRI) and receptor II (sTNFRII) levels. (B) Soluble interleukin 1 receptor I (sIL-1RI) and receptor II (sIL-1RII) levels. (C) Interleukin 6 (IL-6), soluble IL-6 receptor (sIL-6R), and sgp130 levels. aCD v HS: *p<0.05, **p<0.01; aCD v rCD: †p<0.05, ††p<0.01; rCD v HS: ‡p<0.05. Results are shown as box plots; the line within the box represents the median value with the outer limits of the box representing the 25th and 75th percentile values; whiskers above and below the box indicate the 90th and 10th percentile values. Statistical comparisons were performed using the Kruskal-Wallis test.

Figure 2

Correlations between soluble interleukin 1 receptor II (sIL-1RII), sgp130, and C reactive protein (CRP) levels in active Crohn’s disease patients before treatment (infliximab or corticosteroids), in Crohn’s disease patients in remission, and in healthy subjects. (A) sIL-1RII and CRP levels. (B) sgp130 and CRP levels. ρ, Spearman’s correlation coefficient; p, significance.

Figure 3

Circulating soluble interleukin 1 receptor II (sIL-1RII) (A) and sgp130 (B) levels in 15 healthy subjects (HS), in 11 patients with ulcerative colitis in clinical remission (rUC), and in 13 patients with active UC (aUC). aCD v HS: *p<0.05; aCD v rCD: †p<0.05. Results are shown as box plots; the line within the box represents the median value with the outer limits of the box representing the 25th and 75th percentile values; whiskers above and below the box indicate the 90th and 10th percentile values. Statistical comparisons were performed using the Kruskal-Wallis test.

Figure 4

Interleukin 1β (IL-1β) (A), IL-6 (B), soluble interleukin 1 receptor II (sIL-1RII) (C), and sgp130 (D) levels in 18 hour culture media of colonic biopsies of healthy (HCM, n = 8), non-inflamed Crohn’s disease (CDnon-inf, n = 7), and inflamed Crohn’s disease mucosa (CDinf, n = 8). CDinf v HCM: **p<0.01; CDinf v CDnon-inf: †p<0.05, ††p<0.01; CDnon-inf v HCM: ‡p<0.05. Results are shown as box plots; the line within the box represents the median value with the outer limits of the box representing the 25th and 75th percentile values; whiskers above and below the box indicate the 90th and 10th percentile values. Statistical comparisons were performed using the Kruskal-Wallis test.

Figure 5

Plasma levels of C reactive protein (CRP) (A), interleukin 6 (IL-6) (B), soluble IL-6 receptor (sIL-6R) (C), and soluble tumour necrosis factor receptor II (sTNFRII) of Crohn’s disease patients with active disease after infliximab administration. Results are expressed as mean (SEM) and statistical comparisons were performed using the Wilcoxon signed rank test. *p<0.05, **p<0.01.

Figure 6

Plasma levels of C reactive protein (CRP) (A), interleukin 6 (IL-6) (B), soluble IL-1 receptor II (sIL-1RII) (C), and soluble IL-1 receptor I (sIL-1RI) (D) in nine Crohn’s disease patients with active disease after corticosteroid administration. Results are expressed as mean (SEM) and statistical comparisons were performed using the Wilcoxon signed rank test. *p<0.05.