Differential induction of TGF-beta regulates proinflammatory cytokine production and determines the outcome of lethal and nonlethal Plasmodium yoelii infections

• Published in: The Journal of immunology (1950) 2003-11, Vol.171 (10), p.5430-5436
• Main Authors: Omer, Fakhreldin M, de Souza, J Brian, Riley, Eleanor M
• Format: Article
• Language: English
• Subjects: Animals; Cell Adhesion - immunology; Cells, Cultured; Cytokines - biosynthesis; Down-Regulation - immunology; Epitopes, T-Lymphocyte - biosynthesis; Immune Sera - administration & dosage; Inflammation Mediators - metabolism; Interferon-gamma - biosynthesis; Malaria - immunology; Malaria - mortality; Malaria - parasitology; Malaria - prevention & control; Malaria Vaccines - administration & dosage; Malaria Vaccines - immunology; Mice; Mice, Inbred C57BL; Parasitemia - immunology; Parasitemia - mortality; Parasitemia - parasitology; Plasmodium yoelii - growth & development; Plasmodium yoelii - immunology; Plasmodium yoelii - pathogenicity; Receptors, Interleukin-2 - biosynthesis; Spleen - cytology; Spleen - immunology; Spleen - metabolism; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Transforming Growth Factor beta - antagonists & inhibitors; Transforming Growth Factor beta - biosynthesis; Transforming Growth Factor beta - immunology; Transforming Growth Factor beta - physiology; Tumor Necrosis Factor-alpha - biosynthesis; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.171.10.5430

Transforming growth factor-beta is an essential moderator of malaria-induced inflammation in mice. In this study, we show that the virulence of malaria infections is dependent upon the cellular source of TGF-beta and the timing of its production. C57BL/6 mice infected with a nonlethal (Py17X) strain of Plasmodium yoelii produce TGF-beta from 5 days postinfection; this correlates with resolution of parasitemia, down-regulation of TNF-alpha, and full recovery. In contrast, infection with the lethal strain Py17XL induces high levels of circulating TGF-beta within 24 h; this is associated with delayed and blunted IFN-gamma and TNF-alpha responses, failure to clear parasites, and 100% mortality. Neutralization of early TGF-beta in Py17XL infection leads to a compensatory increase in IL-10 production, while simultaneous neutralization of TGF-beta and IL-10R signaling leads to up-regulation of TNF-alpha and IFN-gamma, prolonged survival in all, and ultimate resolution of infection in 40% of Py17XL-infected animals. TGF-beta production can be induced in an Ag-specific manner from splenocytes of infected mice, and by cross-linking surface CTLA-4. CD25(+) and CD8(+) cells are the primary source of TGF-beta following Py17X stimulation of splenocytes, whereas Py17XL induces significant production of TGF-beta from adherent cells. In mice immunized against Py17XL, the early TGF-beta response is inhibited and is accompanied by significant up-regulation of IFN-gamma and TNF-alpha and rapid resolution of challenge infections.