Mechanism of IL-10 production via IL-1R in gut macrophages

Inflammatory bowel disease (IBD) is a chronic condition characterized by intestinal immune imbalance. Gut macrophages help maintain homeostasis by producing interleukin-10 (IL-10), which prevents excessive immune responses. However, the mechanism of IL-10 production remains unclear. This study hypothesized that an IL-1 receptor (IL-1R)-dependent pathway, independent of gut microbes, contributes to IL-10 production in gut macrophages. We compared Il10 expression in gut macrophages from germ-free (GF) and specific-pathogen-free (SPF) wild-type mice and SPF MyD88 knockout (KO) mice. Il1r1 expression was assessed, and IL-1β stimulation was tested on murine gut macrophages and RAW 264.7 cells overexpressing IL-1R1. We analyzed the involvement of MyD88, p38, ERK, and CREB in IL-1R1 signaling using small interfering RNA (siRNA). Il10 expression did not differ between GF and SPF wild-type mice but decreased in MyD88 KO mice. Il1r1 expression was higher in gut macrophages than in other macrophage types. IL-1β stimulation induced Il10 expression and IL-10 production in IL-1R1-overexpressing RAW 264.7 cells, activating p38, ERK, and CREB. Suppression of MyD88 or CREB reduced Il10 expression and IL-10 production. These findings suggest that the IL-1β/IL-1R-MyD88-CREB pathway, involving p38 and ERK, functions as a microbe-independent IL-10 production mechanism in gut macrophages, sharing signaling cascades with bacterial lipopolysaccharide pathways. Further studies using human gut macrophages are needed to explore their relevance to IBD pathogenesis.