TRAF5 Deficiency Ameliorates the Severity of Dextran Sulfate Sodium Colitis by Decreasing TRAF2 Expression in Nonhematopoietic Cells

• Published in: ImmunoHorizons Vol. 4; no. 3; pp. 129 - 139
• Main Authors: Phung, Hai The, Nagashima, Hiroyuki, Kobayashi, Shuhei, Asano, Naoki, Machiyama, Tomoaki, Sakurai, Tsuyoshi, Tayama, Shun-Ichi, Asao, Atsuko, Imatani, Akira, Kawabe, Takeshi, Okuyama, Yuko, Ishii, Naoto, So, Takanori
• Format: Journal Article
• Language: English
• Published: United States 10-03-2020
• ISSN: 2573-7732; 2573-7732
• DOI: 10.4049/immunohorizons.2000007

TNFR-associated factor 5 (TRAF5) is a cytosolic adaptor protein and functions as an inflammatory regulator. However, the in vivo function of TRAF5 remains unclear, and how TRAF5 controls inflammatory responses in the intestine is not well understood. In this study, we found that intestinal epithelial cells from
mice expressed a significantly lower level of NF-κB-regulated proinflammatory genes, such as
,
, and
, as early as day 3 after dextran sulfate sodium (DSS) exposure when compared with wild-type mice. The intestinal barrier integrity of DSS-treated
mice remained intact at this early time point, and
mice showed decreased body weight loss and longer colon length at later time points. Surprisingly, the protein level of TRAF2, but not TRAF3, was reduced in colon tissues of
mice after DSS, indicating the requirement of TRAF5 for TRAF2 protein stability in the inflamed colon. Experiments with bone marrow chimeras confirmed that TRAF5 deficiency in nonhematopoietic cells caused the attenuated colitis. Our in vitro experiments demonstrated that proinflammatory cytokines significantly promoted the degradation of TRAF2 protein in
nonhematopoietic cells in a proteasome-dependent manner. Collectively, our data suggest a novel regulatory function of TRAF5 in supporting the proinflammatory function of TRAF2 in nonhematopoietic cells, which may be important for acute inflammatory responses in the intestine.