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 target genes such as interleukin-6 (IL-6), TNF-alpha, and IL-8. In particular, Wip1 reduction of TNF-alpha expression was shown to be through dephosphorylation of NF-kappaB, whereas Wip1 inhibition of IL-6 and IL-8 expression occurred through inhibition of p38 (Figure 6). Therefore, Wip1 appears to play a role in inflammation similar to that after genotoxic stress, i.e., Wip1 helps to turn off the inflammatory response (Figure 4 and Figure 6). Furthermore, taken together with the study from Lowe et al. (5), this describes another negative feedback loop involving Wip1. Wip1 is induced by NF-kappaB activated by inflammatory stimuli, and then Wip1 negatively regulates NF-kappaB signaling to reduce the inflammatory response (Figure 6).
