| First Author | De Santis S | Year | 2017 |
| Journal | Cell Death Dis | Volume | 8 |
| Issue | 8 | Pages | e2993 |
| PubMed ID | 28796256 | Mgi Jnum | J:341169 |
| Mgi Id | MGI:7531896 | Doi | 10.1038/cddis.2017.397 |
| Citation | De Santis S, et al. (2017) TNFalpha deficiency results in increased IL-1beta in an early onset of spontaneous murine colitis. Cell Death Dis 8(8):e2993 |
| abstractText | Inflammatory bowel disease (Crohn's disease (CD) and ulcerative colitis (UC)) is a multifactorial disease resulting from immune dysregulation in the gut. The underlying colitis is characterized by high levels of inflammatory cytokines, including TNFalpha. Biological intervention for IBD patients using anti-TNFalpha antibodies is often an effective therapeutic solution. However, TNFalpha neutralization fails to induce remission in a subgroup of IBD patients, primarily in UC patients. There is a dearth of suitable animal models representing TNFalpha non-responders. Here we have combined one of the best UC models currently available, namely Winnie and the TNFalphaKO mouse to generate a TNFalpha-deficient Winnie to study early onset colitis. The induced TNFalpha deficiency with underlying colitis does not influence general health (viability and body weight) or clinical parameters (colon weight, colon length and histological colitis) when compared with the Winnie genotype alone. The molecular characterization resulted in identification of Il1beta as the major elevated cytokine during early phases of colitis. Further, in vitro functional assay using bone marrow-derived dendritic cells confirmed IL-1beta as the major cytokine released in the absence of TNFalpha. This study has generated a successful model of colitis that remains TNFalpha non-responsive and has demonstrated that IL-1beta expression is a major pathway for the progression of colitis in this system. These data also suggest that IL-1beta can be a potential target for clinical intervention of UC patients who fail to respond to TNFalpha neutralization. |
