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. 2015 Aug;129(3):281-90.
doi: 10.1042/CS20150176.

Interleukin 34: A New Modulator of Human and Experimental Inflammatory Bowel Disease

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Free PMC article

Interleukin 34: A New Modulator of Human and Experimental Inflammatory Bowel Disease

Stephanie Zwicker et al. Clin Sci (Lond). .
Free PMC article

Abstract

IBD (inflammatory bowel disease), where CD (Crohn's disease) and UC (ulcerative colitis) represent the two main forms, are chronic inflammatory conditions of the intestine. Macrophages play a central role in IBD pathogenesis and are regulated by major differentiation factors such as CSF-1 (colony-stimulating factor 1) in homoeostasis and inflammation. IL (interleukin)-34 has recently been discovered as a second ligand for CSF-1R (CSF-1 receptor). However, expression and involvement of IL-34 in IBD remain unknown. In the present paper, we investigated the expression of IL34, CSF1 and their shared receptor CSF1R in normal human ileum and colon, in inflamed and non-inflamed tissues of CD and UC patients, and in a mouse model of experimental colitis. We found distinct expression patterns of IL34 and CSF1 in ileum and colon, with higher IL34 in ileum and, in contrast, higher CSF1 in colon. Furthermore, IL34 and CSF1 expression was increased with inflammation in IBD patients and in experimental colitis. In humans, infiltrating cells of the lamina propria and intestinal epithelial cells expressed IL-34, and TNF-α (tumour necrosis factor α) regulated IL-34 expression in intestinal epithelial cells through the NF-κB (nuclear factor κB) pathway. These data demonstrate the expression pattern of IL-34 in ileum and colon and suggest IL-34 as a new modulator of inflammation in IBD.

Figures

Figure 1
Figure 1. IL34, CSF1 and CSF1R are differently expressed in normal human ileum and colon
(A) IL34, (B) CSF1 and (C) CSF1R relative mRNA expression in ileum and colon, presented as the mean per colon sites for each patient. (D) IL34, (E) CSF1 and (F) CSF1R relative mRNA in different sites of the colon. Correlations between (G and J) IL34 and CSF1, (H and K) IL34 and TNFA, and (I and L) CSF1 and TNFA in ileum (GI) and colon (JL). Comparisons between ileum and colon were calculated using Mann–Whitney U tests, and between different sites of colon by ANOVA with post-hoc LSD tests. Correlations were assessed by Spearman's correlation coefficients. n=24 for ileum, n=29 for colon. Results are means±S.E.M. *P≤0.05; **P≤0.01; ***P≤0.001.
Figure 2
Figure 2. Increased expression of IL34, CSF1 and CSF1R in inflamed compared with non-inflamed colon of patients with IBD
(A) IL34, (B) CSF1 and (C) CSF1R relative mRNA expression in colon presented as the mean per colon sites for each patient in IBD patients subdivided into CD and UC. Comparisons were calculated by Mann–Whitney U tests. n=21 for non-inflamed IBD, n=34 for inflamed IBD, n=13 for non-inflamed CD, n=8 for non-inflamed CD, n=17 for non-inflamed UC, n=24 for inflamed UC. Results are means±S.E.M. *P≤0.05; **P≤0.01; ***P≤0.001.
Figure 3
Figure 3. Presence of IL-34 in gut epithelium, and NF-κB-dependent regulation of TNF-α-induced IL34 and CSF1 expression in colon epithelial cells
(A) Immunohistochemical staining of human colon showing the presence of IL-34 and isotype control. (B) TNF-α (1–100 ng/ml) up-regulates IL34 gene expression at 6 h. (C) Blocking NF-κB with celastrol down-regulates IL34 expression in colon epithelial cells. (D) The presence of IL-34 shown by immunofluorescent staining of intestinal epithelial cells following TNF-α stimulation. Comparisons were calculated by ordinary one-way ANOVA. Results are means±S.E.M. for two to four individual experiments. *P≤0.05; **P≤0.01; ***P≤0.001.
Figure 4
Figure 4. IL-34- and CSF-1-differentiated macrophages show regulated expression of TNFA, IL1B and IL-10, whereas pro-inflammatory cytokines are increased in monocytes from patients with IBD
Regulated expression of TNFA, IL1B and IL10 by (AC) IL-34 and (DF) CSF-1 induced differentiation of macrophages (day 8). Expression of (G) TNFA, (H) IL1B and (I) IL10 in CSF-1- and IL-34-differentiated macrophages. Expression of (J) IL34, (K) CSF1, (L) TNFA and (M) IL1B in monocytes from IBD patients and controls. The differentiation experiment was performed twice with similar results. n=6 for control monocytes, n=10 for IBD-monocytes. Results are means±S.E.M. *P≤0.05; **P≤0.01; ***P≤0.001.
Figure 5
Figure 5. Increased expression of Il34 and Csf1 in DSS-induced colitis in mice
(A) Il34 and (B) Csf1 relative mRNA expression in colon on day 5. (C) Correlation between Il34 and Csf1 in colons of DSS-treated mice on day 5. (D) Il34 (E) Csf1 relative mRNA expression in colon on day 26. (F) Correlation between Il34 and Csf1 in colons of DSS-treated mice on day 26. The experiment was performed twice with similar results. Results are means±S.E.M. Correlations were assessed by Spearman's correlation coefficients. NT, non-treated. *P≤0.05; **P≤0.01; ***P≤0.001.

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