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

S De Santis, D Kunde, V Galleggiante, M Liso, L Scandiffio, G Serino, A Pinto, P Campiglia, R Sorrentino, E Cavalcanti, A Santino, M L Caruso, R Eri, M Chieppa

Research output: Contribution to journalArticlepeer-review

Abstract

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 TNFα. Biological intervention for IBD patients using anti-TNFα antibodies is often an effective therapeutic solution. However, TNFα neutralization fails to induce remission in a subgroup of IBD patients, primarily in UC patients. There is a dearth of suitable animal models representing TNFα non-responders. Here we have combined one of the best UC models currently available, namely Winnie and the TNFαKO mouse to generate a TNFα-deficient Winnie to study early onset colitis. The induced TNFα 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 Il1β as the major elevated cytokine during early phases of colitis. Further, in vitro functional assay using bone marrow-derived dendritic cells confirmed IL-1β as the major cytokine released in the absence of TNFα. This study has generated a successful model of colitis that remains TNFα non-responsive and has demonstrated that IL-1β expression is a major pathway for the progression of colitis in this system. These data also suggest that IL-1β can be a potential target for clinical intervention of UC patients who fail to respond to TNFα neutralization.

Original languageEnglish
Pages (from-to)e2993
Number of pages7
JournalCell Death and Disease
Volume8
Issue number8
DOIs
Publication statusPublished - Aug 10 2017

Keywords

  • Journal Article

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