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Negative Regulation of Bacterial fMLP-induced Pro-inflammatory Cytokine Gene Expression via MKP-1-dependent Inhibition of NF-Ò¡B

Ling-Yu Chen, Xiaying Lu, Xiaohuan Chen, Hallie Dolin, Karen Pan, Thomas J. Papadimos, Yong Jiang and Zhixing K. Pan

The stimulated release of pro inflammatory cytokines (i.e. TNFα and IL-1β) by bacterial fMet-Leu-Phe- (fMLP) in human peripheral blood monocytes and macrophages is an important component of the inflammatory process and plays a critical role in sepsis and septic shock. The signaling mechanisms utilized by fMLP to stimulate the release of cytokines are still incompletely understood. We previously demonstrated that the key positive signaling pathways involved in the activation of nuclear factor ?B (NF-?B) and the resultant inflammatory response by bacterial fMLP. We now present evidence that MKP- 1, a MAP kinase phosphatase, negatively regulates fMLP-induced NF-?Bdependent inflammatory response both in vitro and in vivo. Interestingly, our data indicate that anti- inflammatory agent, dexamethasone, a synthetic member of the glucocorticoid class of hormones, inhibits fMLP-induced TNFα in monocytes through increasing MKP-1 expression, which occurs at the level of IKK via the glucocorticoid receptor (GR). These results suggest a potential role of MKP-1 in the regulation of pro inflammatory cytokine expression, and provide the first evidence that such regulation may occur through the NF-?B pathway in fMLP-stimulated human peripheral blood monocytes.