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Infection and Immunity, August 1999, p. 4055-4063, Vol. 67, No. 8
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Activation of Phosphotyrosine Phosphatase Activity Attenuates Mitogen-Activated Protein Kinase Signaling and Inhibits c-FOS and Nitric Oxide Synthase Expression in Macrophages Infected with Leishmania donovani

Devki Nandan,1,2 Raymond Lo,1,2 and Neil E. Reiner1,2,3,*

Department of Medicine (Division of Infectious Diseases), Faculty of Medicine,1 and Department of Microbiology and Immunology, Faculty of Science,3 University of British Columbia, and Research Institute of the Vancouver Hospital and Health Sciences Center,2 Vancouver, British Columbia, Canada V5Z 3J5

Received 19 January 1999/Returned for modification 2 March 1999/Accepted 19 May 1999

Intracellular protozoan parasites of the genus Leishmania antagonize host defense mechanisms by interfering with cell signaling in macrophages. In this report, the impact of Leishmania donovani on mitogen-activated protein (MAP) kinases and nitric oxide synthase (NOS) expression in the macrophage cell line RAW 264 was investigated. Overnight infection of cells with leishmania led to a significant decrease in phorbol-12-myristate-13-acetate (PMA)-stimulated MAP kinase activity and inhibited PMA-induced phosphorylation of the MAP kinase substrate and transcription factor Elk-1. Simultaneously, leishmania infection markedly attenuated the induction of c-FOS and inducible nitric oxide synthase (iNOS) expression in response to PMA and gamma interferon (IFN-gamma ), respectively. These effects correlated with decreased phosphorylation of p44 and p42 MAP kinases on tyrosine residues. Consistent with the latter finding, lysates prepared from leishmania-infected cells contained an activity that dephosphorylated MAP kinase in vitro, suggesting the possibility of a phosphatase acting in vivo. Attenuation of both MAP kinase activity and c-FOS and iNOS expression was reversed by treatment of macrophages with sodium orthovanadate prior to infection. It was also found that the specific activity of the Src homology 2 domain containing tyrosine phosphatase (SHP-1) toward MAP kinase was markedly increased in leishmania-infected cells. These findings indicate that infection with L. donovani attenuates MAP kinase signaling and c-FOS and iNOS expression in macrophages by activating cellular phosphotyrosine phosphatases. This may represent a novel mechanism of macrophage deactivation during intracellular infection.

* Corresponding author. Mailing address: Division of Infectious Diseases, Department of Medicine, University of British Columbia, Room 452D, 2733 Heather St., Vancouver, British Columbia, Canada V5Z 3J5. Phone: (604) 875-4011. Fax: (604) 875-4013. E-mail: ethan{at}interchange.ubc.ca.

Infection and Immunity, August 1999, p. 4055-4063, Vol. 67, No. 8
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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