TNFα deficiency results in increased IL-1β in an early onset of spontaneous murine colitis

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 TNF<i>α</i>. Biological intervention for IBD patients using anti-TNF<i>α</i> antibodies is often an effective therapeutic solution. However, TNF<i>α</i> neutralization fails to induce remission in a subgroup of IBD patients, primarily in UC patients. There is a dearth of suitable animal models representing TNF<i>α</i> non-responders. Here we have combined one of the best UC models currently available, namely <i>Winnie</i> and the TNF<i>α</i>KO mouse to generate a TNF<i>α</i>-deficient <i>Winnie</i> to study early onset colitis. The induced TNF<i>α</i> 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 <i>Winnie</i> genotype alone. The molecular characterization resulted in identification of Il1<i>β</i> as the major elevated cytokine during early phases of colitis. Further, <i>in vitro</i> functional assay using bone marrow-derived dendritic cells confirmed IL-1<i>β</i> as the major cytokine released in the absence of TNF<i>α</i>. This study has generated a successful model of colitis that remains TNF<i>α</i> non-responsive and has demonstrated that IL-1<i>β</i> expression is a major pathway for the progression of colitis in this system. These data also suggest that IL-1<i>β</i> can be a potential target for clinical intervention of UC patients who fail to respond to TNF<i>α</i> neutralization.