Glucocorticoids synergize with IL-1β to induce TLR2 expression via MAP Kinase Phosphatase-1-dependent dual Inhibition of MAPK JNK and p38 in epithelial cells

We show that IL-1β, a key proinflammatory cytokine, greatly up-regulates TLR2 expression in human epithelial cells via a positive IKKβ-IκBα-dependent NF-κB pathway and negative MEKK1-MKK4/7-JNK1/2 and MKK3/6-p38 α/β pathways. Glucocorticoids synergistically enhance IL-1β-induced TLR2 expression via specific up-regulation of the MAP kinase phosphatase-1 that, in turn, leads to dephosphorylation and inactivation of both MAPK JNK and p38, the negative regulators for TLR2 induction.These results indicate that glucocorticoids not only suppress immune and inflammatory response, but also enhance the expression of the host defense receptor, TLR2. Thus, our studies may bring new insights into the novel role of glucocorticoids in orchestrating and optimizing host immune and defense responses during bacterial infections and enhance our understanding of the signaling mechanisms underlying the glucocorticoid-mediated attenuation of MAPK.Epithelial cells are often situated at host-environment boundaries, and thus act as the first line of defense against bacterial pathogens [1]. The epithelial cells are not merely a passive barrier but can detect foreign pathogens and generate a range of mediators that play important roles in the activation of innate and adaptive immunity. For effective host defense, the epithelial cells recognize highly conserved structural motifs only expressed by microbial pathogens, called pathogen-associated molecular patterns (PAMPs). Toll-like receptors (TLRs) play a critical role in early innate immunity to invading microorganisms by sensing PAMPs [2]. Stimulation of TLRs by PAMPs initiates a signaling cascade that induces the production and secretion of proinflammatory cytokines [3]. Moreover, stimulation of TLRs also induces the production of effector cytokines that leads to activation of adaptive immunity.Mammalian TLRs were originally found as homologues of the Drosophila Toll [4]. TLRs are type I transmembrane receptors, that possess extracellular leu