Cylindromatosis (CYLD) is a deubiquitinating enzyme that is altered in patients 
with familial cylindromatosis, a condition characterized by numerous benign 
adnexal tumors. However, the regulatory function of CYLD remains unsettled. Here 
we show that the development of B cells, T cells, and myeloid cells was 
unaffected in CYLD-deficient mice, but that the activation of these cells with 
mediators of innate and adaptive immunity resulted in enhanced NF-kappaB and JNK 
activity associated with increased TNF receptor-associated factor 2 (TRAF2) and 
NF-kappaB essential modulator (NEMO) ubiquitination. CYLD-deficient mice were 
more susceptible to induced colonic inflammation and showed a dramatic increase 
in the incidence of tumors compared with controls in a colitis-associated cancer 
model. These results suggest that CYLD limits inflammation and tumorigenesis by 
regulating ubiquitination in vivo.