title: Glucocorticoids synergistically enhance nontypeable Haemophilus influenzae-induced Toll-like receptor 2 expression via a negative cross-talk with p38 MAP kinase.
abstract: The recognition of invading microbes followed by the induction of effective innate immune response is crucial for host survival. Human surface epithelial cells are situated at host-environment boundaries and thus act as the first line of host defense against invading microbes. They recognize the microbial ligands via Toll-like receptors (TLRs) expressed on the surface of epithelial cells. TLR2 has gained importance as a major receptor for a variety of microbial ligands. In contrast to its high expression in lymphoid tissues, TLR2 is expressed at low level in epithelial cells. Thus, it remains unclear whether the low amount of TLR2 expressed in epithelial cells is sufficient for mediating bacteria-induced host defense and immune response and whether TLR2 expression can be up-regulated by bacteria during infection. Here, we show that TLR2, although expressed at very low level in unstimulated human epithelial cells, is greatly up-regulated by nontypeable Hemophilus influenzae (NTHi), an important human bacterial pathogen causing otitis media and chronic obstructive pulmonary diseases. Activation of an IKKbeta-IkappaBalpha-dependent NF-kappaB pathway is required for TLR2 induction, whereas inhibition of the MKK3/6-p38alpha/beta pathway leads to enhancement of NTHi-induced TLR2 up-regulation. Surprisingly, glucocorticoids, well known potent anti-inflammatory agents, synergistically enhance NTHi-induced TLR2 up-regulation likely via a negative cross-talk with the p38 MAP kinase pathway. These studies may bring new insights into the role of bacteria and glucocorticoids in regulating host defense and immune response and lead to novel therapeutic strategies for modulating innate immune and inflammatory responses for otitis media and chronic obstructive pulmonary diseases.
authors.affiliation: Gonda Department of Cell and Molecular Biology, House Ear Institute, and the Department of Otolaryngology, University of Southern California, Los Angeles, CA 90057, USA.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shuto
authors.forename: Akira
authors.initials: A
authors.lastname: Imasato
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Jono
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sakai
authors.forename: Haidong
authors.initials: H
authors.lastname: Xu
authors.forename: Takahiro
authors.initials: T
authors.lastname: Watanabe
authors.forename: Davida D
authors.initials: DD
authors.lastname: Rixter
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kai
authors.forename: Ali
authors.initials: A
authors.lastname: Andalibi
authors.forename: Fred
authors.initials: F
authors.lastname: Linthicum
authors.forename: Yue-Ling
authors.initials: YL
authors.lastname: Guan
authors.forename: Jiahuai
authors.initials: J
authors.lastname: Han
authors.forename: Andrew C B
authors.initials: AC
authors.lastname: Cato
authors.forename: David J
authors.initials: DJ
authors.lastname: Lim
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Li
mesh_terms: D001426:Bacterial Proteins; D015153:Blotting, Western; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D029721:Drosophila Proteins; D004847:Epithelial Cells / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism*; D006193:Haemophilus influenzae / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins; D020935:MAP Kinase Signaling System; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D000072000:NF-KappaB Inhibitor alpha; D018272:Porins / Q000378:metabolism*; D021381:Protein Transport; D011956:Receptors, Cell Surface / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014162:Transfection; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D005938:Glucocorticoids; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D008562:Membrane Glycoproteins; C000606204:NFKBIA protein, human; D018272:Porins; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; C451502:ompP2 protein, Haemophilus influenzae; D000072000:NF-KappaB Inhibitor alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases