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Infection and Immunity, March 1999, p. 1347-1352, Vol. 67, No. 3
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Gamma Interferon Stimulates Rat Alveolar Macrophages To Kill Pneumocystis carinii by L-Arginine- and Tumor Necrosis Factor-Dependent Mechanisms

James F. Downing,dagger Diane L. Kachel, Rajamouli Pasula, and William J. Martin II*

Division of Pulmonary, Allergy, Critical Care and Occupational Medicine, Department of Medicine, Indiana University Medical Center, Indianapolis, Indiana 46202-2879

Received 30 July 1998/Returned for modification 24 August 1998/Accepted 15 December 1998

Pneumocystis carinii pneumonia remains a serious complication for immunocompromised patients. In the present study, P. carinii organisms interacted with gamma interferon (IFN-gamma )-stimulated alveolar macrophages (AMs) to activate the L-arginine-dependent cytocidal pathway involving reactive nitrogen intermediates (RNI) that were assayed as nitrite (NO2-). Unstimulated cultures of AMs produced negligible quantities of RNI. Addition of P. carinii organisms to IFN-gamma -primed AMs resulted in greatly enhanced production of RNI. NO2- levels increased from 0.8 ± 0.4 to 11.1 ± 3.8 µM as early as 6 h after P. carinii organisms were incubated with IFN-gamma -stimulated AMs and to 35.1 ± 8.9 µM after a 24-h incubation, a near-maximum level. High levels of NO2- were produced by AMs primed with as little as 10 U of IFN-gamma per ml in the presence of P. carinii, and a 20-fold increase in IFN-gamma concentration resulted in only a further 65% increase in NO2- production. RNI-dependent killing of P. carinii was demonstrated by both a 51Cr release assay and a [35S]methionine pulse immunoprecipitation assay. Addition of either monoclonal tumor necrosis factor alpha (TNF-alpha ) neutralizing antibody or 200 µM NG-monomethyl-L-arginine (L-NGMMA), a competitive inhibitor of the L-arginine-dependent pathway, significantly decreased NO2- production and reduced P. carinii killing. TNF-alpha alone had no effect on P. carinii viability. These results suggest that (i) the specific interaction of P. carinii organisms with IFN-gamma -primed AMs triggers the production of RNI, (ii) RNI are toxic to P. carinii, and (iii) TNF-alpha likely plays a central role in mediating P. carinii killing by IFN-gamma -stimulated AMs.

* Corresponding author. Mailing address: Department of Internal Medicine, Division of Pulmonary, Allergy, Critical Care and Occupational Medicine, 1001 West 10th St., OPW 425, Indianapolis, IN 46202-2879. Phone: (317) 630-8445. Fax: (317) 630-6386. E-mail: wjmartin{at}iupui.edu.

dagger Present address: Indiana Nephrology, Kokomo, IN 46902.

Infection and Immunity, March 1999, p. 1347-1352, Vol. 67, No. 3
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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