FGL2 regulates IKK/NF-κB signaling in intestinal epithelial cells and lamina propria dendritic cells to attenuate dextran sulfate sodium-induced colitis.

Inflammatory bowel disease (IBD) is an autoimmune disease characterized by an abnormal immune response. Fibrinogen-like protein 2 (FGL2) is known to have immunoregulatory and anti-inflammatory activity. The level of FGL2 is elevated in patients with IBD; however, its comprehensive function in IBD is almost unknown. In our study, we explored the effect of FGL2 on dextran sulfate sodium (DSS)-induced colitis in mice and on NF-κB signaling in intestinal epithelial cells (IECs) and lamina propria dendritic cells (LPDCs). We founded that FGL2 mice in the colitis model showed more severe colitis manifestations than WT mice did, including weight loss, disease activity index (DAI), and colon histological scores. FGL2 mice treated with DSS produced more proinflammatory cytokines (IL-1β, IL-6, TNF-α) in serum than WT mice did and demonstrated upregulated expression of TNF-α and inflammatory marker enzymes, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (Cox-2) in the colon tissue. Our data suggested that DSS-treated FGL2 mice showed stronger activation of NF-κB signaling, especially in IECs. Next, we demonstrated that recombinant FGL2 (rFGL2) inhibited the production of proinflammatory cytokines and the expression of inflammatory marker enzymes by downregulating the NF-κB signaling in HT-29 cells. Finally, we discovered that LPDCs from the colon of DSS-treated FGL2 mice showed significantly upregulated expression of surface maturation co-stimulatory molecules, including CD80, CD86, CD40, and MHC class II molecules compared with that in WT mice. In addition, LPDCs in FGL2 treated with DSS exhibited excessive NF-κB activity and the administration of rFGL2 to FGL2 mice could rescue the aggravated results of FGL2 mice. Taken together, our findings demonstrated that FGL2 might be a target for further therapy of IBD.