Glucocorticoids synergistically enhance nontypeable Haemophilus influenzae-induced toll-like receptor 2 expression via a negative cross-talk with p38 MAP kinase

Tsuyoshi Shuto, Akira Imasato, Hirofumi Jono, Akihiro Sakai, Haidong Xu, Takahiro Watanabe, Davida D. Rixter, Hirofumi Kai, Ali Andalibi, Fred Linthicum, Yue Ling Guan, Jiahuai Han, Andrew C.B. Cato, David J. Lim, Shizuo Akira, Jian Dong Li

Research output: Contribution to journalArticle

127 Scopus citations

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 upregulated 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 IKKβ-IκBα-dependent NF-κB pathway is required for TLR2 induction, whereas inhibition of the MKK3/6-p38α/β 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.

Original languageEnglish (US)
Pages (from-to)17263-17270
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number19
DOIs
StatePublished - May 10 2002

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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