Glucocorticoids synergize with IL-1beta to induce TLR2 expression via MAP Kinase Phosphatase-1-dependent dual Inhibition of MAPK JNK and p38 in epithelial cells.
BACKGROUND
Despite the importance of glucocorticoids in suppressing immune and inflammatory responses, their role in enhancing host immune and defense response against invading bacteria is poorly understood. Toll-like receptor 2 (TLR2) has recently gained importance as one of the major host defense receptors. The increased expression of TLR2 in response to bacteria-induced cytokines has been thought to be crucial for the accelerated immune response and resensitization of epithelial cells to invading pathogens.


RESULTS
We show that IL-1beta, a key proinflammatory cytokine, greatly up-regulates TLR2 expression in human epithelial cells via a positive IKKbeta-IkappaBalpha-dependent NF-kappaB pathway and negative MEKK1-MKK4/7-JNK1/2 and MKK3/6-p38 alpha/beta pathways. Glucocorticoids synergistically enhance IL-1beta-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.


CONCLUSIONS
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.
Sakai
Akihiro
A
Gonda Department of Cell and Molecular Biology, House Ear Institute, and University of Southern California, Los Angeles, CA 90057, USA. asakai@hei.org
Han
Jiahuai
J
Cato
Andrew C B
AC
Akira
Shizuo
S
Li
Jian-Dong
JD
D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D004357:Drug Synergism; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase; D017874:Immediate-Early Proteins / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D020033:Protein Isoforms / Q000235:genetics; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D018797:Cell Cycle Proteins; D005938:Glucocorticoids; D017874:Immediate-Early Proteins; D007375:Interleukin-1; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D003907:Dexamethasone; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases