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Platelet-activating factor receptor and ADAM10 mediate responses to Staphylococcus aureus in epithelial cells

Nature Medicine volume 8, pages 41–46 (2002)Cite this article

Abstract

In the lungs of cystic fibrosis patients, overproduction of mucus leads to morbidity and mortality by obstructing airflow and shielding bacteria from antibiotics. Here we demonstrate that overproduction of mucus is a direct result of the activation of mucin gene expression by Gram-positive bacteria. Bacterial lipoteichoic acid activates the platelet-activating factor receptor, which is G protein–coupled. This results in activation of a disintegrin and metalloproteinase (ADAM10), kuzbanian, cleavage of pro heparin–binding epidermal growth factor and activation of the epidermal growth factor receptor. Unlike responses in macrophages, the epithelial-cell response to lipoteichoic acid does not require Toll-like receptor 2 or 4.

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Figure 1: Gram-positive bacteria stimulate mucin synthesis.
Figure 2: LTA stimulates PAFR; this is required for mucin induction.
Figure 3: Transactivation of EGFR and mucin induction by LTA requires PAFR, metalloproteinases and HB-EGF.
Figure 4: TLRs are required for LTA responses in monocytes but not epithelial cells.
Figure 5: LTA and LPS signaling converge at Ras to induce mucin; rat model.
Figure 6: This model combines our earlier results on Gram negative–induced signaling in epithelial cells3 with results from this study.

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Acknowledgements

We thank R. Medzhitov for providing the Myd88 mutant MyDC; Z. Werb and D. Julius for discussion; M. Gallup, E. Drori and S. Sidhu for collaboration. This work was supported by NIH grants HL43726 and HL 24136 as well as by a grant from the Cystic Fibrosis Foundation.

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  1. Cardiovascular Research Institute and Department of Anatomy, Biomedical Sciences Program, University of California, San Francisco, California, USA

    Hassan Lemjabbar & Carol Basbaum

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  1. Hassan Lemjabbar
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Correspondence to Carol Basbaum.

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Lemjabbar, H., Basbaum, C. Platelet-activating factor receptor and ADAM10 mediate responses to Staphylococcus aureus in epithelial cells. Nat Med 8, 41–46 (2002). https://doi.org/10.1038/nm0102-41

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