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Infection and Immunity, December 2002, p. 6672-6679, Vol. 70, No. 12
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.12.6672-6679.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Transgenic Mice Expressing Human Interleukin-10 in the Antigen-Presenting Cell Compartment Show Increased Susceptibility to Infection with Mycobacterium avium Associated with Decreased Macrophage Effector Function and Apoptosis

Carl G. Feng,1* Marika C. Kullberg,1 Dragana Jankovic,1 Allen W. Cheever,2 Patricia Caspar,1 Robert L. Coffman,3 and Alan Sher1

Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda,1 Biomedical Research Institute, Rockville, Maryland,2 Dynavax Technologies, Berkeley, California3

Received 10 June 2002/ Returned for modification 30 July 2002/ Accepted 17 September 2002

Interleukin-10 (IL-10) is thought to play an important role in the regulation of microbial immunity. While T-cell-derived IL-10 has been shown to suppress cell-mediated immunity, there has been debate as to whether antigen presenting cell (APC)-derived cytokine can perform the same function in vivo. To assess the influence of APC-produced IL-10 on host resistance to mycobacterial infection, transgenic mice expressing human IL-10 under the control of the major histocompatibility complex class II promoter (hu10Tg) were infected with Mycobacterium avium, and bacterial burdens and immune responses were compared with those observed in wild-type (wt) animals. Hu10Tg mice harbored substantially higher numbers of M. avium and succumbed 16 to 18 weeks postinfection. The granulomas in infected hu10Tg mice showed marked increases in both acid-fast bacilli and host macrophages. In addition, these animals displayed a dramatic increase in hepatic fibrosis. The increased susceptibility of the hu10Tg mice to M. avium infection is independent of T-cell-produced endogenous murine IL-10, since bacterial burdens in mice derived by crossing hu10Tg mice with murine IL-10-deficient mice were not significantly different from those in hu10Tg mice. Importantly, gamma interferon (IFN-{gamma}) responses were not decreased in the infected transgenic animals from those in wt animals, suggesting the normal development of Th1 effector cells. In contrast, mycobacterium-induced macrophage apoptosis as well as production of TNF, nitric oxide, and IL-12p40 were strongly inhibited in hu10Tg mice. Together, these data indicate that APC-derived IL-10 can exert a major inhibitory effect on control of mycobacterial infection by a mechanism involving the suppression of macrophage effector function and apoptosis.

* Corresponding author. Mailing address: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 50 Room 6148, 50 South Dr., Bethesda, MD 20892-8003. Phone: (301) 594-2890. Fax: (301) 402-0890. E-mail: cfeng{at}niaid.nih.gov.

Editor: J. M. Mansfield

Infection and Immunity, December 2002, p. 6672-6679, Vol. 70, No. 12
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.12.6672-6679.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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