Immunomodulatory role of chloroquine and pyrimethamine in Plasmodium yoelii 17XL infected mice.
Chloroquine (CLQ) and Pyrimethamine (PYR) are used for the treatment of malaria and some autoimmune diseases; although their mechanism of action is only partially understood, their therapeutic effectiveness in the second case has been attributed to their ability to increase apoptosis of T lymphocytes. In view of the potential for immunomodulation during malaria chemotherapy, we investigated the effects of CLQ and PYR treatment on lymphocyte apoptosis and cytokine expression during infection with blood-stage Plasmodium. This work shows that infection of BALB/c mice with Plasmodium yoelii 17XL (Py17XL) reduced apoptosis in spleen cells but when infected mice were treated with CLQ, apoptosis of B and T lymphocytes increased significantly via a Fas-mRNA expression independent mechanism associated with downregulation of Bcl-2 expression, whereas treatment with PYR increased apoptosis to a lesser extent and only in B lymphocytes. CLQ treatment of Py17XL infected mice upregulated tumour necrosis factor-alpha mRNA expression, while PYR treatment increased interferon-gamma mRNA expression. In infected mice, treatment with CLQ downregulated expression of the anti-inflammatory cytokines, interleukin-10 and transforming growth factor-beta (TGF-beta), while PYR treatment upregulated TGF-beta. Thus, in addition to their anti-malarial effects, both drugs modulate the immune response in malaria by increasing apoptosis and modulating the mRNA expression of cytokines involved in parasite elimination and regulation of inflammatory responses.
Ramos-Avila
A
A
Laboratorio de Inmunología Molecular, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, México D.F.
Ventura-Gallegos
J L
JL
Zentella-Dehesa
A
A
Machuca-Rodríguez
C
C
Moreno-Altamirano
M M
MM
Narváez
V
V
Legorreta-Herrera
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics; D007155:Immunologic Factors / Q000494:pharmacology*; D008288:Malaria / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010967:Plasmodium yoelii; D011739:Pyrimethamine / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D017382:Reactive Oxygen Species / Q000378:metabolism
D016207:Cytokines; D007155:Immunologic Factors; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D002738:Chloroquine; D011739:Pyrimethamine