Fig. 6.

Model of MKP-1-mediated temporal regulation of cytokine production in TLR signaling. Macrophage activation is divided into two phases: an initial phase characterized by rapid production of proinflammatory cytokines such as TNF-α and a second phase that involves the synthesis of IL-10. In the first phase, p38 MAPK and JNK are rapidly activated (≈20 min) and contribute to the expression of TNF-α. This early event is followed by the induction of MKP-1 (≈60 min) mediated by MyD88 and TRIF pathways, which serves as a negative feedback mechanism to down-regulate p38 MAPK and JNK activities and TNF-α production. In the second phase, activities of JNK and p38 MAPK are reduced because of MKP-1 but still higher than basal levels, whereas MKP-1 expression is suppressed to allow the remaining active p38 MAPK and JNK to promote IL-10 expression. IL-10, in turn, further limits TNF-α expression. For simplicity, only pathways relevant to MKP-1 are shown.