Published online 23 December 2008
Haematologica, Vol 94, Issue 2, 195-204 doi:10.3324/haematol.13422
Copyright © 2009 by Ferrata Storti Foundation
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Malarial Anemia

STAT6-mediated suppression of erythropoiesis in an experimental model of malarial anemia

Neeta Thawani1,2, Mifong Tam1, Mary M. Stevenson1,2

1 Centre for the Study of Host Resistance, Research Institute of the McGill University Health Centre and
2 Centre for Host-Parasite Interactions, Institute of Parasitology, McGill University, Montreal, Quebec, Canada

Correspondence: Mary M. Stevenson Ph.D., Centre for the Study of Host, Resistance, Research Institute, of the McGill University Health, Centre, Rm. L11-409, 1650, Cedar Ave, Montreal, Quebec, H3G 1A4, Canada., E-mail:mary.m.stevenson{at}mcgill.ca

Background: The contribution of pro-inflammatory cytokines to the pathogenesis of malarial anemia has been studied extensively but the roles of Th2 cytokines remain unknown. Here, we investigated the role of signal transducer and activator of transcription (STAT)6-mediated responses in erythropoietic suppression during acute malaria infection in mice.

Design and Methods: Naïve and/or erythropoietin-treated wild-type and STAT6–/– mice were infected with Plasmodium chabaudi AS (P. chabaudi), and the effects parasitemia, hematologic parameters, erythropoietin receptor, TER119, and CD71 expression, in vitro erythropoietin-stimulated proliferation of splenic erythroid precursors, and serum cytokine levels were analyzed. To explore the role of interleukin-4 in STAT6-dependent erythropoietic suppression, mice were treated in vivo with a monoclonal antibody to interleukin-4 and the effects on parasitemia, hematologic parameters, and cytokine levels were analyzed.

Results: Infected STAT6–/– mice developed enhanced reticulocytosis compared to wild-type mice despite higher parasitemia and a similar course of anemia. Enhanced reticulocytosis in infected STAT6–/– mice was associated with an increased frequency of late-stage erythroblasts, fewer leukocytes expressing CD71, and increased erythropoietin-stimulated proliferation of splenocytes compared to infected wild-type mice. Interleukin-4-depleted wild-type mice had increased levels of parasitemia and a course of reticulocytosis similar to responses observed in infected STAT6–/– mice. Determination of serum cytokine levels in STAT6–/– and wild-type mice depleted of interleukin-4 by treatment with mAb revealed significantly lower levels of interferon-{gamma} compared to control wild-type mice during infection.

Conclusions: Together, these findings provide evidence for a STAT6-dependent mechanism in mediating erythropoietic suppression during acute blood-stage malaria and indicate a role for interleukin-4 and possibly interferon-{gamma}in STAT6-induced erythropoietic suppression.

Key words: malaria, anemia, erythropoiesis, STAT6, interleukin-4, interferon-{gamma}.


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