Interleukin-34 sustains inflammatory pathways in the gut

Inflammatory bowel disease (IBD)-related tissue damage occurs in areas, which are massively infiltrated with monocytes/macrophages. These cells respond to inflammatory stimuli with enhanced production of cytokines/chemokines. In this study, we analyzed the expression and role of interleukin-34 (IL-34), a regulator of monocyte/macrophage differentiation, survival and function, in IBD. A significant increase in IL-34 mRNA and protein expression was seen in inflamed mucosa of patients with Crohn's disease (CD) and patients with ulcerative colitis (UC) as compared to the uninvolved areas of the same patients and normal controls. IL-34 was up-regulated in lamina propria mononuclear cells (LPMC) isolated from normal colon by TNF-a and toll-like receptor ligands and wasdown-regulated in intestinal biopsies and LPMC of IBD patients upon treatment with Infliximab. Treatment of normal LPMC with IL-34 increased TNF-αexpression in an ERK1/2-dependent fashion and neutralization of IL-34 in IBD mucosal explants reduced TNF-α and IL-6 synthesis. In conclusion, data indicate that IL-34 is up-regulated in IBD and suggest a role for this cytokine in sustaining the inflammatory responses in this disease.