Published ahead of print on July 15, 2004, doi:10.1165/rcmb.2003-0433OC Am. J. Respir. Cell Mol. Biol., Volume 31, Number 5, November 2004, 528-537 A more recent version of this article appeared on November 1, 2004
Submitted on December 3, 2003 EGF and TFF2 Synergisticly Trigger Chemotaxis on BEAS-2B Cells via Different Signalling CascadesCaroline E Chwieralski1,1 Institute for Molecular Biology and Medical Chemistry, Otto-von-Guericke-University, Medical Faculty, Magdeburg, Germany, 2 Department of Protein Chemistry, Novo Nordisk A/S, Bagsvaerd, Denmark * To whom correspondence should be addressed. E-mail: Werner.Hoffmann{at}Medizin.Uni-Magdeburg.de.
Injured areas of the respiratory epithelium are subject to rapid repair by the migration of adjacent epithelial cells, a process termed "restitution". Rapid re-epithelialization is promoted by interactions between migrating cells and the extracellular matrix (ECM) proteins. Furthermore, epidermal growth factor (EGF) as well as trefoil factor family (TFF) peptides are well known regulators of epithelial restitution due to their motogenic effects. Migration of the human bronchial epithelial cell line BEAS-2B in modified Boyden chambers was used as a model system for airway restitution. EGF or recombinant human TFF2 or TFF3 showed mainly chemotactic activity. The motogenic response was strictly dependent upon a haptotactic substrate, but to different degrees. EGF was able to induce phosphorylation of ERK1/2, JNK, p38, Akt, and p70S6K in BEAS-2B cells. Using specific inhibitors, the signaling cascades responsible for the motogenic response were shown to differ drastically when EGF was compared with TFF2. The motogenic effect of TFF2 was previously demonstrated to depend on ERK1/2 and protein kinase C (PKC) activation; whereas the EGF-triggered motogenic response was completely independent of ERK1/2 activation, but sensitive to the inhibition of phosphoinositide 3-kinase (PI3K), p38, PKC, or NF-
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B. However, the motogenic effects of EGF and TFF2 are additive. These data suggest that luminal EGF and TFF peptides can act synergisticly in the human respiratory epithelium to enhance rapid repair processes in the course of diseases such as asthma.
