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Infection and Immunity, May 2004, p. 2477-2483, Vol. 72, No. 5
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.5.2477-2483.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Differential Regulation of DAP12 and Molecules Associated with DAP12 during Host Responses to Mycobacterial Infection

Naoko Aoki, Anna Zganiacz, Peter Margetts, and Zhou Xing*

Infectious Diseases Division, Center for Gene Therapeutics, and Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada L8N 3Z5

Received 19 September 2003/ Returned for modification 17 November 2003/ Accepted 29 January 2004

DAP12 and its associating molecules MDL-1, TREM-1, and TREM-2 are the recently identified immune regulatory molecules, expressed primarily on myeloid cells including monocytes/macrophages, dendritic cells, NK cells, and neutrophils. However, little is known about the regulation of their expression during host antimicrobial responses. We have investigated the effect of pulmonary mycobacterial infection and type 1 cytokines on the expression of these molecules both in vivo and in vitro. While DAP12 was constitutively expressed at high levels in the lungs, the MDL-1, TREM-1, and TREM-2 molecules were inducible during mycobacterial infection. Their kinetic expression was correlated with that of the type 1 cytokines tumor necrosis factor alpha (TNF-{alpha}) and gamma interferon (IFN-{gamma}). In primary lung macrophage cultures, high constitutive levels of DAP12 and TREM-2 were not modulated by mycobacterial or type 1 cytokine exposure. In contrast, expression of both MDL-1 and TREM-1 was markedly induced by mycobacterial infection and such induction was inhibited by concurrent exposure to IFN-{gamma}. On mycobacterial infection of TNF-{alpha}–/– and IFN-{gamma}–/– mice in vivo or their lung macrophages in vitro, TNF-{alpha} was found to be critical for mycobacterially induced MDL-1, but not TREM-1, expression whereas IFN-{gamma} negatively regulated mycobacterially induced MDL-1 and TREM-1 expression. Our findings thus suggest that DAP12 and its associating molecules are differentially regulated by mycobacterial infection and type 1 cytokines and that MDL-1- and TREM-1-triggered DAP12 signaling may play an important role in antimicrobial type 1 immunity.

* Corresponding author. Mailing Address: Department of Pathology and Molecular Medicine, Rm. 4H19-Health Sciences Centre, McMaster University, 1200 Main St. West, Hamilton, Ontario, Canada L8N 3Z5. Phone: (905) 525-9140, ext. 22354. Fax: (905) 522-6750. E-mail: xingz{at}mcmaster.ca.

Editor: S. H. E. Kaufmann

Infection and Immunity, May 2004, p. 2477-2483, Vol. 72, No. 5
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.5.2477-2483.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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