Exacerbated Experimental Colitis in TNFAIP8-Deficient Mice

Abstract

The TNF-α-induced protein 8 (TNFAIP8 or TIPE) is a risk factor for cancer and bacterial infection, and its expression is upregulated in a number of human cancers. However, its physiological and pathological functions are unclear. We describe here the generation of TIPE-deficient mice and their increased sensitivity to colonic inflammation. TIPE-deficient mice were generated by germ line gene targeting and were born without noticeable developmental abnormalities. Their major organs including lymphoid organs and intestines were macroscopically and microscopically normal. However, after drinking dextran sodium sulfate-containing water, TIPE-deficient mice developed more severe colitis than wild type mice, as demonstrated by decreased survival rates, increased body weight loss, and enhanced leukocyte infiltration, bacterial invasion, and inflammatory cytokine production in the colon. Bone marrow chimeric experiments revealed that TIPE deficiency in non-hematopoietic cells was responsible for the exacerbated colitis in TIPE-deficient mice. Consistent with this result, TIPE-deficient intestinal epithelial cells had increased rate of cell death and decreased rate of proliferation as compared to wild type controls. Taken together, these findings indicate that TIPE plays an important role in maintaining colon homeostasis and in protecting against colitis.

The TIPE Molecular Pilot That Directs Lymphocyte Migration in Health and Inflammation

“…3). This is consistent with our previous report that C57BL/6 mice deficient in either TIPE2 or TNFAIP8 alone do not have significant changes in their total lymphocyte numbers in lymphoid organs under the steady state (before 10 weeks of age) 24,27 . These results indicate that, under steady state, directed migration is critical for T cell deployment to lymphoid organs, and that random migration (which can be significantly enhanced by chemokines) also plays an important role in leukocyte deployment to lymphoid organs.…”

Regulation of inflammation and tumorigenesis by the TIPE family of phospholipid transfer proteins

“…37 Knocking out the TNFAIP8 gene also exacerbated disease in a dextran sodium sulfate (DSS) model of murine colitis, and the data suggested that this effect was due to decreased epithelial cell survival in the face of the chemical insult. 38 Knocking down TNFAIP8 also excacerbates oxidative stress-mediated autophagic cell death in a manner involving decreased mTOR activation. 39 In contrast to the aforementioned studies, the downregulation of TNFAIP8 has also been shown to prevent glucocorticoid-mediated apoptosis in thymocytes.…”

Fasting-Mimicking Diet Modulates Microbiota and Promotes Intestinal Regeneration to Reduce Inflammatory Bowel Disease Pathology

“…The DAI for each animal was recorded once after every 5-day DSS administration period for the first two DSS cycles, and then every day starting after the third DSS cycle. Scores were determined based on body weight loss, stool consistency, and rectal bleeding as described previously (Sun et al, 2015). Body weight loss was scored as follows: score 0, no body weight loss; score 1, body weight loss within 1%−5%; score 2, body weight loss within 5%−10%; score 3, body weight loss within 10%−20%; score 4, greater than 20% body weight loss.…”