3 research outputs found
The role of activins in hepcidin regulation during malaria
Epidemiological observations have linked increased host iron with malaria susceptibility, and perturbed iron handling has been hypothesized to contribute to the potentially life threatening anemia that may accompany blood-stage malaria infection. To improve our understanding of these relationships, we examined the pathways involved in regulation of the master controller of iron metabolism, the hormone hepcidin, in malaria infection. We show that hepcidin upregulation in Plasmodium berghei murine malaria infection was accompanied by changes in expression of bone morphogenetic protein (BMP)/sons of mothers against decapentaplegic (SMAD) pathway target genes, a key pathway involved in hepcidin regulation. We therefore investigated known agonists of the BMP/SMAD pathway, and found that Bmp gene expression was not increased in infection. In contrast, activin B, which can signal through the BMP/SMAD pathway and has been associated with increased hepcidin during inflammation, was upregulated in the livers of Plasmodium berghei infected mice; hepatic activin B was also upregulated at peak parasitemia during infection with Plasmodium chabaudi. Concentrations of the closely related protein activin A increased in parallel with hepcidin in serum from malaria-naΓ―ve volunteers infected in controlled human malaria infection (CHMI) clinical trials. However, antibody-mediated neutralization of activin activity during murine malaria infection did not affect hepcidin expression, suggesting that these proteins are unlikely to stimulate hepcidin upregulation directly. In conclusion, we present evidence that the BMP/SMAD signalling pathway is perturbed in malaria infection, but that activins, although raised in malaria infection, may not have a critical role in hepcidin upregulation in this setting
The role of activins in hepcidin regulation during malaria
Epidemiological observations have linked increased host iron with malaria
susceptibility, and perturbed iron handling has been hypothesized to contribute to
the potentially life threatening anemia that may accompany blood-stage malaria
infection. To improve our understanding of these relationships, we examined the
pathways involved in regulation of the master controller of iron metabolism, the
hormone hepcidin, in malaria infection. We show that hepcidin upregulation in
Plasmodium berghei murine malaria infection was accompanied by changes in
expression of bone morphogenetic protein (BMP)/sons of mothers against
decapentaplegic (SMAD) pathway target genes, a key pathway involved in
hepcidin regulation. We therefore investigated known agonists of the BMP/SMAD
pathway, and found that Bmp gene expression was not increased in infection. In
contrast, activin B, which can signal through the BMP/SMAD pathway and has
been associated with increased hepcidin during inflammation, was upregulated in
the livers of Plasmodium berghei infected mice; hepatic activin B was also
upregulated at peak parasitemia during infection with Plasmodium chabaudi.
Concentrations of the closely related protein activin A increased in parallel with
hepcidin in serum from malaria-naΓ―ve volunteers infected in controlled human
malaria infection (CHMI) clinical trials. However, antibody-mediated neutralization
of activin activity during murine malaria infection did not affect hepcidin
expression, suggesting that these proteins are unlikely to stimulate hepcidin
upregulation directly. In conclusion, we present evidence that the BMP/SMAD
signalling pathway is perturbed in malaria infection, but that activins, although
raised in malaria infection, may not have a critical role in hepcidin upregulation in
this setting