Abstract
In murine bone marrow macrophages, lipopolysaccharide (LPS) induces apoptosis through the autocrine production of tumor necrosis factor-alpha (TNF-alpha), as demonstrated by the fact that macrophages from TNF-alpha receptor I knock-out mice did not undergo early apoptosis. In these conditions LPS up-regulated the two concentrative high affinity nucleoside transporters here shown to be expressed in murine bone marrow macrophages, concentrative nucleoside transporter (CNT) 1 and 2, in a rapid manner that is nevertheless consistent with the de novo synthesis of carrier proteins. This effect was not dependent on the presence of macrophage colony-stimulating factor, although LPS blocked the macrophage colony-stimulating factor-mediated up-regulation of the equilibrative nucleoside transport system es. TNF-alpha mimicked the regulatory response of nucleoside transporters triggered by LPS, but macrophages isolated from TNF-alpha receptor I knock-out mice similarly up-regulated nucleoside transport after LPS treatment. Although NO is produced by macrophages after LPS treatment, NO is not involved in these regulatory responses because LPS up-regulated CNT1 and CNT2 transport activity and expression in macrophages from inducible nitric oxide synthase and cationic amino acid transporter (CAT) 2 knock-out mice, both of which lack inducible nitric oxide synthesis. These data indicate that the early proapoptotic responses of macrophages, involving the up-regulation of CNT transporters, follow redundant regulatory pathways in which TNF-alpha-dependent- and -independent mechanisms are involved. These observations also support a role for CNT transporters in determining extracellular nucleoside availability and modulating macrophage apoptosis.
Highlights
D Supported by a fellowship from Programa BEFI (Fondo de Investigacion Sanitaria, Ministerio de Sanidad, Spain)
In murine bone marrow macrophages, lipopolysaccharide (LPS) induces apoptosis through the autocrine production of tumor necrosis factor-␣ (TNF-␣), as demonstrated by the fact that macrophages from TNF-␣ receptor I knock-out mice did not undergo early apoptosis. In these conditions LPS up-regulated the two concentrative high affinity nucleoside transporters here shown to be expressed in murine bone marrow macrophages, concentrative nucleoside transporter (CNT) 1 and 2, in a rapid manner that is consistent with the de novo synthesis of carrier proteins
The early apoptotic events triggered by LPS were mediated by the autocrine production of TNF-␣ by macrophages because cells isolated from TNF-␣ receptor I knock-out mice were protected from apoptosis after LPS treatment (Fig. 1)
Summary
D Supported by a fellowship from Programa BEFI (Fondo de Investigacion Sanitaria, Ministerio de Sanidad, Spain). Porter (CAT) 2 knock-out mice, both of which lack inducible nitric oxide synthesis These data indicate that the early proapoptotic responses of macrophages, involving the up-regulation of CNT transporters, follow redundant regulatory pathways in which TNF-␣dependent- and -independent mechanisms are involved. These observations support a role for CNT transporters in determining extracellular nucleoside availability and modulating macrophage apoptosis. Macrophage activation and apoptosis appear to be modulated by extracellular nucleosides and nucleotides (7–12) These effects are partially explained by their interaction with adenosine and P2 receptors, respectively. Considering that nucleoside transport is necessary either to generate active metabolites intracellularly or to modulate adenosine availability to its receptors, nucleoside transporters may be elements of these regulatory networks, which are key determinants of macrophage activation during septic shock
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