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J. Biol. Chem., Vol. 277, Issue 40, 37054-37063, October 4, 2002

This Article Full Text Full Text (PDF) All Versions of this Article: 277/40/37054    most recent M205778200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Propst, S. M. Articles by Schwiebert, L. M. Search for Related Content PubMed PubMed Citation Articles by Propst, S. M. Articles by Schwiebert, L. M. Social Bookmarking                      What's this?

CD40-mediated Activation of NF-B in Airway Epithelial Cells^*

Stacie M. Propst, Kim Estell, and Lisa M. Schwiebert

From the Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294

We have reported previously that airway epithelial cells (AEC) express CD40 and that activation of this molecule stimulates the expression of inflammatory mediators, including the chemokine RANTES (regulated on activation normal T cell expressed and secreted). Because NF-B regulates the expression of many inflammatory mediators, such as RANTES, we utilized CD40-mediated induction of RANTES expression to investigate the mechanisms that underlie CD40-mediated activation of NF-B in AEC. Results demonstrate that, in AEC, intact NF-B sites were required for CD40-mediated activation of the RANTES promoter. To examine activation of NF-B binding directly, electrophoretic mobility shift analyses were performed. These analyses revealed that CD40 ligation stimulated NF-B binding and that the activated NF-B complexes were composed of p65 subunits. Additional studies focused on the CD40-triggered signaling pathways that facilitate NF-B activation. Findings show that CD40 engagement activated the IB kinases IKK- and IKK- and stimulated IB phosphorylation. Analyses also examined the role of tumor necrosis factor-associated factor (TRAF) molecules in CD40-mediated NF-B activation within AEC. Stable transfectants expressing wild-type or mutant forms of the cytoplasmic domain of CD40 suggested that TRAF3, but not TRAF2, binding was essential for CD40-mediated RANTES expression. Further studies indicated that exogenous expression of wild-type TRAF3 enhanced activation of the RANTES promoter, whereas exogenous expression of wild-type TRAF2 inhibited this activation; TRAF3-mediated enhancement was dependent upon NF-B. Together, these findings suggest that, in AEC, ligation of CD40 regulates the expression of inflammatory mediators, such as RANTES, via activation of NF-B. Moreover, these results suggest that CD40-mediated signaling in AEC differs with previously reported findings observed in other cell models, such as B lymphocytes.

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