Fig. 2. Physiological roles of DUSP1/MKP-1 in immunity and metabolic regulation. (A) In macrophages, LPS signals through Toll-like receptor (TLR), which engages the adaptor proteins MyD88 and TRIF. This leads to an early response, in which p38 MAPK and JNK are activated and contribute to the expression of TNF, and is followed by induction of MKP-1 expression, which serves to downregulate p38/JNK activities and TNF production. At later times, as MKP-1 expression declines, the levels of p38 MAPK and JNK activity remain higher than in unstimulated cells and promote IL10 expression. (B) In insulin-responsive tissues, MKP-1 regulates multiple MAPK pathways in the nucleus, and thus controls the expression of genes involved in fatty acid metabolism and energy expenditure. The activities of MAPKs in the cytosol are not subject to regulation by MKP-1. Therefore, negative feedback controls, such as the phosphorylation of IRS by JNK, are unaffected.