Elsevier

Laboratory Investigation

Volume 93, Issue 9, September 2013, Pages 1024-1035
Laboratory Investigation

Article
Protective role of tumor necrosis factor (TNF) receptors in chronic intestinal inflammation: TNFR1 ablation boosts systemic inflammatory response

https://doi.org/10.1038/labinvest.2013.89Get rights and content
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Abstract

Tumor necrosis factor-α (TNF-α) acts as a key factor for the development of inflammatory bowel diseases (IBDs), whose function is known to be mediated by TNF receptor 1 (TNFR1) or TNFR2. However, the precise role of the two receptors in IBD remains poorly understood. Herein, chronic colitis was established by oral administration of dextran sulfate sodium (DSS) in TNFR1 or TNFR2−/− mice. Unexpectedly, TNFR1 or TNFR2 deficiency led to exacerbation of signs of colitis compared with wild-type (WT) counterparts. Of note, TNFR1 ablation rendered significantly increased mortality compared with TNFR2 and WT mice after DSS. Aggravated pathology of colitis in TNFR1−/− or TNFR2−/− mice correlated with elevated colonic expression of proinflammatory cytokines and chemokines. Importantly, ablation of TNFR1 or TNFR2 increased apoptosis of colonic epithelial cells, which might be due to the heightened ratio of Bax/Bcl-2 and increased expression of caspase-8. Intriguingly, despite comparable intensity of intestinal inflammation in TNFR-deficient mice after DSS, systemic inflammatory response (including splenomegaly and myeloid expansion) was augmented dramatically in TNFR1−/− mice, instead of TNFR2−/− mice. Granulocyte-macrophage colony-stimulating factor (GMCSF) was identified as a key mediator in this process, as neutralization of GMCSF dampened peripheral inflammatory reaction and reduced mortality in TNFR1−/− mice. These data suggest that signaling via TNFR1 or TNFR2 has a protective role in chronic intestinal inflammation, and that lacking TNFR1 augments systemic inflammatory response in GMCSF-dependent manner.

apoptosis
colitis
granulocyte macrophage colony-stimulating factor
systemic inflammatory response
TNF receptor

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Tumor necrosis factor (TNF) deficiency exacerbates the severity of experimental chronic colitis. TNF receptor 1 (TNFR1) −/−, but not TNFR2−/− mice, show increased mortality and augmented systemic inflammatory response compared to wild-type littermates. Granulocyte-macrophage colony-stimulating factor (GMCSF) is a key mediator in this process. Signaling via TNFR therefore plays a protective role in chronic intestinal inflammation, and the lack of TNFR1 augments a systemic inflammatory response in GMCSF-dependent manner.

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Yi Wang, Gencheng Han and Yu Chen: These authors contributed equally to this work.