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

Mol Immunol. 2020 Jan;117:84-93. doi: 10.1016/j.molimm.2019.11.001. Epub 2019 Nov 16.

Abstract

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.

Keywords: Fibrinogen-like protein 2; Inflammatory bowel disease; Intestinal epithelial cells; NF-κB; lamina propria dendritic cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Colitis / chemically induced
  • Colitis / immunology*
  • Colitis / metabolism
  • Dendritic Cells / immunology*
  • Dextran Sulfate / toxicity
  • Fibrinogen / immunology*
  • Fibrinogen / metabolism
  • I-kappa B Kinase / immunology
  • Intestinal Mucosa / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mucous Membrane / immunology
  • NF-kappa B / immunology
  • Signal Transduction / immunology*

Substances

  • Fgl2 protein, mouse
  • NF-kappa B
  • Fibrinogen
  • Dextran Sulfate
  • I-kappa B Kinase