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Infection and Immunity, April 2003, p. 2095-2101, Vol. 71, No. 4
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.4.2095-2101.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Leishmania donovani-Induced Expression of Suppressor of Cytokine Signaling 3 in Human Macrophages: a Novel Mechanism for Intracellular Parasite Suppression of Activation

Sylvie Bertholet,1,{dagger} Harold L. Dickensheets,2 Faruk Sheikh,2 Albert A. Gam,1 Raymond P. Donnelly,2 and Richard T. Kenney1*

Division of Bacterial, Parasitic, and Allergenic Products,1 Division of Therapeutic Proteins, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 208922

Received 30 July 2002/ Returned for modification 6 November 2002/ Accepted 24 December 2002

Leishmania donovani protozoan parasites, the causative agent of visceral leishmaniasis, establish an infection partly by interfering with cytokine signaling in the host macrophages. Therefore, we investigated the expression of the suppressor of cytokine signaling (SOCS) genes in human macrophages infected with L. donovani. The expression of SOCS3 mRNA was induced transiently after exposure to live or heat-killed parasites, but not purified lipophosphoglycan, while that of other SOCS genes remained unchanged. SOCS3 gene expression was not dependent on phagocytosis or on cytokines released by L. donovani-infected macrophages, such as interleukin-1ß or tumor necrosis factor alpha. In addition, Leishmania used a different signaling pathway(s) than bacterial lipopolysaccharide to induce SOCS3 mRNA, as indicated by the kinetics of induction and sensitivity to polymyxin B inhibition. Finally, phosphorylation of the STAT1 transcription factor was significantly reduced in L. donovani-infected macrophages and required de novo transcription. The induction of SOCS3 provides a potent inhibitory mechanism by which intracellular microorganisms may suppress macrophage activation and interfere with the host immune response.

* Corresponding author. Present address: Iomai Corporation, 20 Firstfield Rd., Suite 250, Gaithersburg, MD 20878. Phone: (301) 556-4521. Fax: (301) 556-4501. E-mail: rkenney{at}iomai.com.

Editor: W. A. Petri, Jr.

{dagger} Present address: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.

Infection and Immunity, April 2003, p. 2095-2101, Vol. 71, No. 4
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.4.2095-2101.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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