Parasite-Mediated Nuclear Factor κ B Regulation in Lymphoproliferation Caused by Theileria parva Infection

Infection of cattle with the protozoan Theileria parva results in uncontrolled T lymphocyte proliferation resulting in lesions resembling multicentric lymphoma. Parasitized cells exhibit autocrine growth characterized by persistent translocation of the transcriptional regulatory factor nuclear factor κ B (NFκ B) to the nucleus and consequent enhanced expression of interleukin 2 and the interleukin 2 receptor. How T. parva induces persistent NFκ B activation, required for T cell activation and proliferation, is unknown. We hypothesized that the parasite induces degradation of the Iκ B molecules which normally sequester NFκ B in the cytoplasm and that continuous degradation requires viable parasites. Using T. parva-infected T cells, we showed that the parasite mediates continuous phosphorylation and proteolysis of Iκ Bα . However, Iκ Bα reaccumulated to high levels in parasitized cells, which indicated that T. parva did not alter the normal NFκ B-mediated positive feedback loop which restores cytoplasmic Iκ Bα . In contrast, T. parva mediated continuous degradation of Iκ Bβ resulting in persistently low cytoplasmic Iκ Bβ levels. Normal Iκ Bβ levels were only restored following T. parva killing, indicating that viable parasites are required for Iκ Bβ degradation. Treatment of T. parva-infected cells with pyrrolidine dithiocarbamate, a metal chelator, blocked both Iκ B degradation and consequent enhanced expression of NFκ B dependent genes. However treatment using the antioxidant N-acetylcysteine had no effect on either Iκ B levels or NFκ B activation, indicating that the parasite subverts the normal Iκ B regulatory pathway down-stream of the requirement for reactive oxygen intermediates. Identification of the critical points regulated by T. parva may provide new approaches for disease control as well as increase our understanding of normal T cell function..

Medienart:	E-Artikel

Erscheinungsjahr:	1997
Erschienen:	1997

Enthalten in:	Zur Gesamtaufnahme - volume:94

Sprache:	Englisch

Beteiligte Personen:	Palmer, Guy H. [VerfasserIn] Machado, Joel [VerfasserIn] Fernandez, Paula [VerfasserIn] Heussler, Volker [VerfasserIn] Perinat, Therese [VerfasserIn]

Links:	Volltext

Themen:	Biological sciences Health sciences Immunology Physical sciences Research-article

Förderinstitution / Projekttitel:

PPN (Katalog-ID):	JST069978603