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Originally published online as doi:10.1189/jlb.0706478 on May 31, 2007

Published online before print May 31, 2007
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(Journal of Leukocyte Biology. 2007;82:488-496.)
© 2007 by Society for Leukocyte Biology

Toll-like receptor 4 (TLR4)-dependent proinflammatory and immunomodulatory properties of the glycoinositolphospholipid (GIPL) from Trypanosoma cruzi

Monica M. Medeiros*, Jaqueline R. Peixoto*, Ana-Carolina Oliveira*, Larissa Cardilo-Reis{dagger}, Vera L. G. Koatz{dagger}, Luc Van Kaer{ddagger}, José O. Previato§, Lúcia Mendonça-Previato§, Alberto Nobrega* and Maria Bellio*,1

Institutos de
* Microbiologia Prof. Paulo de Góes,
{dagger} Bioquímica Médica, and
§ Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ) CCS, Cidade Universitária, Rio de Janeiro, RJ, Brazil; and
{ddagger} Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

1 Correspondence: Depto. de Imunologia, Instituto de Microbiologia Prof. Paulo de Góes (IMPPG), Universidade Federal do Rio de Janeiro (UFRJ), CCS Bloco I, 2° andar Sala: I2-051, Avenida Carlos Chagas Filho, 373, Cidade Universitária, Ilha do Fundão, CEP: 21941-902, Rio de Janeiro, RJ, Brazil. E-mail: belliom{at}acd.ufrj.br

ABSTRACT

We have demonstrated recently that the glycoinositolphospholipid (GIPL) molecule from the protozoan Trypanosoma cruzi is a TLR4 agonist with proinflammatory effects. Here, we show that GIPL-induced neutrophil recruitment into the peritoneal cavity is mediated by at least two pathways: one, where IL-1ß acts downstream of TNF-{alpha}, and a second, which is IL-1ß- and TNFRI-independent. Moreover, NKT cells participate in this proinflammatory cascade, as in GIPL-treated CD1d–/– mice, TNF-{alpha} and MIP-2 levels are reduced significantly. As a consequence of this inflammatory response, spleen and lymph nodes of GIPL-treated mice have an increase in the percentage of T and B cells expressing the CD69 activation marker. Cell-transfer experiments demonstrate that T and B cell activation by GIPL is an indirect effect, which relies on the expression of TLR4 by other cell types. Moreover, although signaling through TNFRI contributes to the activation of B and {gamma}{delta}+ T cells, it is not required for increasing CD69 expression on {alpha}ß+ T lymphocytes. It is interesting that T cells are also functionally affected by GIPL treatment, as spleen cells from GIPL-injected mice show enhanced production of IL-4 following in vitro stimulation by anti-CD3. Together, these results contribute to the understanding of the inflammatory properties of the GIPL molecule, pointing to its potential role as a parasite-derived modulator of the immune response during T. cruzi infection.

Key Words: neutrophils • TNF-{alpha} • IL-1ß • {gamma}{delta} T cells • CD69




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