TL1A aggravates cytokine-induced acute gut inflammation and potentiates infiltration of intraepithelial natural killer cells in mice

Abstract

Background: The tumor necrosis factor alpha (TNF?)-homologous cytokine TL1A is emerging as a major player in intestinal inflammation. From in vitro experiments on human lymphocytes, TNF-like molecule 1A (TL1A) is known to activate a highly inflammatory lymphoid response in synergy with interleukin (IL)-12 and IL-18. Carriers of specific genetic polymorphisms associated with IL-12, IL-18, or TL1A signaling have increased Crohn's disease risk, and all 3 cytokines are upregulated during active disease. The study aim was to investigate whether the type 1-polarizing cytokines IL-12 and IL-18 could directly initiate intestinal pathology in mice and how TL1A would influence the resulting inflammatory response. Methods: Conventional barrier-bred and germ-free mice were randomly allocated to different groups and injected twice with different combinations of IL-12, IL-18, and TL1A, and killed 3 days after the first injection. All treatment groups were co-housed and fed a piroxicam-supplemented chow diet. Results: Intestinal pathology was evident in IL-12-and IL-18-Treated mice and highly exacerbated by TL1A in both the colon and ileum. The cytokine-induced intestinal inflammation was characterized by epithelial damage, increased colonic levels of TNF?, IL-1?, IFN-?, and IL-6, and various chemokines along with gut microbiota alterations exhibiting high abundance of Enterobacteriaceae. Furthermore, the inflamed ileum and colon exhibited a TL1A-specific increased infiltration of intraepithelial natural killer cells co-expressing NKG2D and IL-18Ra and a higher frequency of unconventional T cells in the colonic epithelium. Upon cytokine injection, germ-free mice exhibited similar intraepithelial lymphoid infiltration and increased colonic levels of IFN? and TNF?. Conclusions: This study demonstrates that TL1A aggravates IL-12-and IL-18-induced intestinal inflammation in the presence and absence of microbiota.