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Induction of Cell Signaling Events by the Cholera Toxin B Subunit in Antigen-Presenting Cells

Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts 02118,¹ Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118²

Received 7 April 2006/ Returned for modification 7 June 2006/ Accepted 3 March 2007

Cholera toxin (CT) is one of the most effective and widely studied mucosal adjuvants. Although the ADP-ribosylating A subunit has been implicated in augmenting immune responses, the receptor-binding B subunit (CT-B) has greater immunogenicity and may be a repository of adjuvant activity without potential toxicity. In order to elucidate mechanisms of immune modulation by CT-B alone, primary B cells and macrophages were assessed for responses to CT-B in vitro, as measured by the expression of cell surface markers, cellular signaling events, and cytokine secretion. Increased phosphorylation of multiple signaling molecules, including Erk1/2 and p38, was detected. CT-B also induced transactivation of the transcription elements cyclic AMP-responsive element and NF-B, the latter of which was inhibited by phosphotyrosine inhibition. While specific inhibition of MEK1/2 did not reduce CT-B induction of cell surface marker expression, it did attenuate CT-B-mediated interleukin-6 secretion. These data show that CT-B induces a set of signaling events related to cellular activation, surface molecule expression, and cytokine production that has potential implications for elucidating CT-B adjuvant activity in the absence of enzymatically active holotoxin.

Published ahead of print on 12 March 2007.

Editor: J. L. Flynn