Inflammation causes several changes in body iron homeostasis, including iron sequestration in the reticuloendothelial system with ensuing hypoferraemia and anemia of chronic disease. A number of inflammatory stimuli have been shown to modulate macrophage iron homeostasis but little is known about the regulation of iron metabolism by anti-inflammatory signals. Adenosine accumulates extracellularly in inflamed areas where it acts as a reporter of tissue damage and activator of anti-inflammatory pathways. We have found that adenosine activates hypoxia inducible factor (HIF1) under normoxic conditions in macrophages (1). HIF1 is a transcription factor that in response to hypoxia turns on the expression of genes important for angiogenesis, glycolysis, cell survival, etc. On the other hand, HIF1 is activated also by typical inflammatory stimuli, such as LPS (2). As we and others have shown that transferrin receptor (TfR) expression is upregulated by HIF1 (3,4), the aim of this study was to understand the interplay between inflammatory and anti-inflammatory modulators on HIF1-mediated TfR expression. Therefore, we investigated the effect of adenosine and LPS/IFNγ on HIF-1-mediated activation of TfR gene expression in macrophages. The expression of TfR was evaluated in mouse macrophage J774A cells exposed to adenosine or specific adenosine receptor agonists/antagonists. Adenosine, through the A2A receptor-dependent pathway, dose-dependently increased TfR protein and mRNA levels and resulted in higher iron uptake. Transfection experiments with a reporter gene under the control of the TfR promoter, DNA and RNA bandshift analysis of HIF1 and iron regulatory proteins binding activity, respectively, indicated a role for transcriptional mechanisms. We also found that exposure of J774A cells to LPS/IFNγ transiently and markedly induced TfR expression at the transcriptional level by means of HIF1 activation. Interestingly, pre-treatment of cells with adenosine prevented the LPS/IFNγ-mediated effect on HIF1 and the consequent increase of TfR expression. Ongoing experiments aimed at understanding the molecular basis of this inhibitory effect of adenosine seem to indicate a role for NF-kB, which transcriptionally controls HIF1 (5) and whose LPS/IFNγ-mediated activation is blunted by adenosine. Post-transcriptional down-modulation of TfR levels has been previously reported in macrophages exposed to LPS/IFNγ, the present data reveal novel mechanisms of transcriptional control of TfR expression regulated by an interplay of inflammatory and anti-inflammatory mediators. The consequent changes of TfR expression could be functionally involved in modulating iron retention in macrophages under inflammatory conditions.