However during inflammation hepcidin appears to be primarily regulated by IL6 [44]. Erlotinib buy Hepcidin (HAMP) inhibits the release of recycled iron from macrophages by binding SLC40A1 (ferroportin) and targeting it for internalization and degradation [45], [46]. Expression of Slc40a1 is also known to be repressed via a TLR4 mediated pathway after stimulation with LPS and IFNG, suggesting that Slc40a1 expression is mediated by both hepcidin-dependent and independent pathways and that the latter may be more important in infections in which the TLR4 pathway is activated. Il6 expression in the liver did not change (not shown). Hamp expression increased slightly post infection in all strains before declining to below baseline levels at day 17 (Fig. 12). Slc40a1 expression in the liver followed that of Hamp (Fig.

12) and declined steadily in the spleen (Not shown). After export by SLC40A1, iron is loaded onto transferrin by Hephaestin, the expression of which remained constant until day 9 (Not shown). These data provide no persuasive evidence for substantial change in iron recycling after infection despite the evidence for a >10 fold increase in macrophage numbers. The relatively steady state expression of iron recycling genes compared with the large increase in expression of macrophage associated genes suggests that iron recycling by individual cells may have declined substantially. Figure 12 Expression of genes involved in iron recycling in the liver. Iron Uptake by macrophages CD163 expression is a scavenger receptor for haptoglobin and haem.

Cd163 expression was high at day zero and then declined >10 fold in both spleen and liver by day 3 to below the threshold of detection (Fig 12). In contrast expression of Slc11a1 (Nramp1), which is a transporter of divalent cations including Fe++, increased about 20 fold between days three and seven (Fig. 12) following the expression of the macrophage and leukocyte markers CD14 and CD45 (Fig. 11). SLC11A1 is a macrophage protein and a metal ion transporter. It has a role in macrophage defense against microbial invasion and the increase in expression may be correlated with macrophage activation to kill parasites by oxidative stress as well as scavenging surplus Fe++ to reduce its abundance in the plasma. Discussion Development of anaemia and other infection parameters were monitored during T.

congolense infections in three inbred mouse strains and associations were made between anaemia development and gene expression profiles. The characteristics of the anaemia in the mouse model used here were very similar to the anaemia in trypanotolerant and susceptible cattle and suggest that the causes of the anaemia are similar in both species. First, the kinetics Brefeldin_A of the anaemia development is similar in both species. The graph of haemoglobin in the three mouse strains studied, indicates two phases of anaemia development.