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Infection and Immunity, May 2005, p. 3115-3123, Vol. 73, No. 5
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.5.3115-3123.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

CD40 Signaling in Macrophages Induces Activity against an Intracellular Pathogen Independently of Gamma Interferon and Reactive Nitrogen Intermediates

Rosa M. Andrade, Jose-Andres C. Portillo, Matthew Wessendarp, and Carlos S. Subauste*

Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267

Received 13 August 2004/ Returned for modification 14 September 2004/ Accepted 20 January 2005

Gamma interferon (IFN-{gamma}) is the major inducer of classical activation of macrophages. Classically activated mouse macrophages acquire antimicrobial activity that is largely dependent on the production of reactive nitrogen intermediates. However, protection against important intracellular pathogens can take place in the absence of IFN-{gamma} and nitric oxide synthase 2 (NOS2). Using Toxoplasma gondii as a model, we investigated if CD40 signaling generates mouse macrophages with effector function against an intracellular pathogen despite the absence of priming with IFN-{gamma} and lack of production of reactive nitrogen intermediates. CD40-stimulated macrophages acquired anti-T. gondii activity that was not inhibited by a neutralizing anti-IFN-{gamma} monoclonal antibody but was ablated by the neutralization of tumor necrosis factor alpha (TNF-{alpha}). Moreover, while the induction of anti-T. gondii activity in response to CD40 stimulation was unimpaired in macrophages from IFN-{gamma}–/– mice, macrophages from TNF receptor 1/2–/– mice failed to respond to CD40 engagement. In contrast to IFN-{gamma}-lipopolysaccharide, CD40 stimulation did not induce NOS2 expression and did not trigger production of reactive nitrogen intermediates. Neither NG-monomethyl-L-arginine nor diphenyleneiodonium chloride affected the induction of anti-T. gondii activity in response to CD40. Finally, macrophages from NOS2–/– mice acquired anti-T. gondii activity in response to CD40 stimulation that was similar to that of macrophages from wild-type mice. These results demonstrate that CD40 induces the antimicrobial activity of macrophages against an intracellular pathogen despite the lack of two central features of classically activated macrophages: priming with IFN-{gamma} and production of reactive nitrogen intermediates.

* Corresponding author. Mailing address: Department of Internal Medicine, University of Cincinnati College of Medicine, P.O. Box 670560, Cincinnati, OH 45267-0560. Phone: (513) 558-0562. Fax: (513) 558-2089. E-mail: carlos.subauste{at}uc.edu.

Editor: J. F. Urban, Jr.

Infection and Immunity, May 2005, p. 3115-3123, Vol. 73, No. 5
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.5.3115-3123.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Zhao, Y., Wilson, D., Matthews, S., Yap, G. S. (2007). Rapid Elimination of Toxoplasma gondii by Gamma Interferon-Primed Mouse Macrophages Is Independent of CD40 Signaling. Infect. Immun. 75: 4799-4803 [Abstract] [Full Text]  
  • Subauste, C. S., Subauste, A., Wessendarp, M. (2007). Role of CD40-Dependent Down-Regulation of CD154 in Impaired Induction of CD154 in CD4+ T Cells from HIV-1-Infected Patients. J. Immunol. 178: 1645-1653 [Abstract] [Full Text]  
  • Subauste, C. S., Wessendarp, M. (2006). CD40 Restrains In Vivo Growth of Toxoplasma gondii Independently of Gamma Interferon. Infect. Immun. 74: 1573-1579 [Abstract] [Full Text]  
  • Andrade, R. M., Wessendarp, M., Portillo, J.-A. C., Yang, J.-Q., Gomez, F. J., Durbin, J. E., Bishop, G. A., Subauste, C. S. (2005). TNF Receptor-Associated Factor 6-Dependent CD40 Signaling Primes Macrophages to Acquire Antimicrobial Activity in Response to TNF-{alpha}. J. Immunol. 175: 6014-6021 [Abstract] [Full Text]  


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