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Infection and Immunity, November 1999, p. 5579-5586, Vol. 67, No. 11
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

The Endogenous Balance of Soluble Tumor Necrosis Factor Receptors and Tumor Necrosis Factor Modulates Cachexia and Mortality in Mice Acutely Infected with Trypanosoma cruzi

Carine Truyens,1 Faustino Torrico,1 Rudolf Lucas,2,dagger Patrick De Baetselier,2 Wim A. Buurman,3 and Yves Carlier1,*

Laboratory of Parasitology, University of Brussels (ULB)1 and Institute for Molecular Biology, Unit of Cellular Immunology, University of Brussels (VUB),2 Brussels, Belgium, and Department of Surgery, Faculty II, University of Limburg, Maastricht, The Netherlands3

Received 11 May 1999/Returned for modification 22 June 1999/Accepted 9 August 1999

To better understand the role of tumor necrosis factor (TNF) during Trypanosoma cruzi infection in BALB/c mice, we have investigated the kinetics of circulating tumor necrosis factor (TNF), soluble TNF receptor 1 (sTNR1), and sTNFR2 levels, as well as the interactions between such factors, in relation to parasitemia, cachexia, and mortality of acutely infected animals. Our data show that the parasitemic phase of T. cruzi infection in mice is associated with high levels of circulating TNF and sTNFR2, resulting in the formation of cytokine-receptor complexes and some degree of neutralization of TNF bioactivity. Although sTNR2 levels always exceeded TNF levels, low sTNFR/TNF circulating ratios were associated with cachexia in all infected mice, whereas the lowest ratios were observed in dying animals harboring the highest parasitemia. We also studied the modulation of sTNFR/TNF ratios induced by anti-TNF antibodies administered to infected animals and their consequences on the outcome of the infection. The injection of anti-TNF monoclonal antibody (MAb) TN3 into infected mice resulted in a paradoxical overproduction of TNF (associated with a higher parasitemia), lowered the sTNFR/TNF circulating ratios, and considerably worsened cachexia and mortality of animals. Another anti-TNF MAb (1F3F3) decreased the in vivo availability of TNF as well as parasite levels and reduced cachexia. Altogether, such results highlight that, besides playing a beneficial role early in infection, TNF also triggers harmful effects in the parasitemic phase, which are limited by the in vivo simultaneous endogenous production of soluble receptors.

* Corresponding author. Mailing address: Laboratoire de Parasitologie, Faculté de Médecine, ULB, Route de Lennik 808, CP 616, B-1070 Brussels, Belgium. Phone: 32 2 555 62 55. Fax: 32 2 555 61 28. E-mail: ycarlier{at}ulb.ac.be.

dagger Present address: Department of Pharmacology, University Medical Centre of Geneva, Geneva, Switzerland.

Infection and Immunity, November 1999, p. 5579-5586, Vol. 67, No. 11
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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