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Clinical and Vaccine Immunology, January 2006, p. 106-115, Vol. 13, No. 1
1071-412X/06/$08.00+0     doi:10.1128/CVI.13.1.106-115.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Cholera Toxin Indirectly Activates Human Monocyte-Derived Dendritic Cells In Vitro through the Production of Soluble Factors, Including Prostaglandin E2 and Nitric Oxide

Kenneth C. Bagley,* Sayed F. Abdelwahab,{dagger} Robert G. Tuskan, and George K. Lewis

Division of Vaccine Research, Institute of Human Virology, University of Maryland Biotechnology Institute, University of Maryland—Baltimore, Baltimore, Maryland 21201

Received 31 August 2005/ Returned for modification 10 October 2005/ Accepted 27 October 2005

Cholera toxin (CT) is a potent adjuvant that activates dendritic cells (DC) by increasing intracellular cyclic AMP (cAMP) levels. In vivo and in vitro, very small amounts of CT induce potent adjuvant effects and activate DC. We hypothesized that DC intoxicated by CT may release factors that enhance their own maturation and induce the maturation of toxin-free bystander DC. Through the use of mixed cultures and transwell cultures, we found that human monocyte-derived DC (MDDC) pulsed with CT or other cAMP-elevating agonists induce the maturation of bystander DC. Many DC agonists including CT increase the production of prostaglandin E2 (PGE2) and nitric oxide (NO). For this reason, we determined whether the actions of PGE2 or NO are involved in the maturation of MDDC induced by CT or dibutyryl-cAMP (d-cAMP). We found that blocking the production of PGE2 or blocking prostaglandin receptors inhibited MDDC maturation induced by CT and d-cAMP. Likewise, sequestering NO or blocking the downstream actions of NO resulted in the inhibition of MDDC maturation induced by CT and d-cAMP. These results indicate that endogenously produced factors including PGE2 and NO contribute to the maturation of DC induced by CT and that these factors participate in bystander DC maturation. The results of this study may help explain why bacterial toxins that elevate cAMP are such potent adjuvants.

* Corresponding author. Present address: Department of Oncology, Johns Hopkins University, 1650 Orleans Street, Baltimore, MD 21231. Phone: (410) 614-3606. Fax: (410) 614-9705. E-mail: kbagley2{at}jhmi.edu.

{dagger} Present address: Department of Microbiology and Immunology, El-minia Faculty of Medicine, El-minia University, El-minia 61111, Egypt.

Clinical and Vaccine Immunology, January 2006, p. 106-115, Vol. 13, No. 1
1071-412X/06/$08.00+0     doi:10.1128/CVI.13.1.106-115.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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