Analysis of the phenotype of Wip1−/− mice provided the first clue that Wip1 may play a role in inflammation. Wip1−/− mice are more susceptible to infection and have a higher frequency of ulcerated skin lesions, and furthermore, splenic lymphocytes harvested from Wip1−/− mice exhibited a dampened proliferative response after stimulation with phytohemagglutinin (PHA) and LPS compared to the wild type controls (74). Additionally, splenocytes from LPS-injected Wip1−/− mice showed a “hyperactivated” phenotype (6). Indeed, inhibition of inflammation was reported as an additional function of Wip1 by Chew et al. (6). Wip1 was shown to suppress the expression of targets of the transcription factor NF-kappaB after cytokine stimulation. Two mechanisms were identified – one through direct inhibition of NF-kappaB (described in section 4.1.1) and the other through inhibition of a previously identified Wip1 target, p38 MAPK. Inhibition of cytokine-induced p38 MAPK activity by Wip1 is presumed to occur through dephosphorylation of T180 of p38, its previously defined function. The functional consequence of Wip1 inhibition of cytokine-induced NF-kappaB and p38 activity was shown to be a reduction in the expression of NF-kappaB
