Adenosine A 2A R and TLR agonists synergize to induce an “angiogenic switch” in macrophages, down-regulating TNF-α and up-regulating VEGF expression. This switch involves transcriptional regulation of VEGF by HIF-1, transcriptional induction of HIF-1α by LPS (TLR4 agonist), and A 2A R-dependent post-transcriptional regulation of HIF-1α stability. Murine HIF-1α is expressed as two mRNA isoforms: HIF-1αI.1 and -I.2, which contain alternative first exons and promoters. HIF-1αI.2 is expressed ubiquitously, and HIF-1αI.1 is tissue-specific. We investigated the regulation of these isoforms in macrophages by TLR4 and A 2A R agonists. HIF-1αI.1 is induced strongly compared with HIF-1αI.2 upon costimulation with LPS and A 2A R agonists (NECA or CGS21680). In unstimulated cells, the I.1 isoform constituted ∼4% of HIF-1α transcripts; in LPS and NECA- or CGS21680-treated macrophages, this level was ∼15%, indicating a substantial contribution of HIF-1αI.1 to total HIF-1α expression. The promoters of both isoforms were induced by LPS but not enhanced further by NECA, suggesting A 2A R-mediated post-transcriptional regulation. LPS/NECA-induced expression of HIF-1αI.1 was down-regulated by Bay 11-7085 (NF-κB inhibitor) and ZM241385 (A 2A R antagonist). Although VEGF and IL-10 expression by HIF-1αI.1−/− macrophages was equivalent to that of wild-type macrophages, TNF-α, MIP-1α, IL-6, IL-12p40, and IL-1β expression was significantly greater, suggesting a role for HIF-1αI.1 in modulating expression of these cytokines. A 2A R expression in unstimulated macrophages was low but was induced rapidly by LPS in a NF-κB-dependent manner. LPS-induced expression of A 2A Rs and HIF-1α and A 2A R-dependent HIF-1α mRNA and protein stabilization provide mechanisms for the synergistic effects of LPS and A 2A R agonists on macrophage VEGF expression.
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Differential regulation of HIF-1α isoforms in murine macrophages by TLR4 and adenosine A2A receptor agonists
Ramanathan, Madhuri; Luo, Wenting; Csóka, Balázs; Haskó, György; Lukashev, Dmitry; Sitkovsky, Michail V.; Leibovich, Samuel Joseph
Follow Journal of Leukocyte Biology
, Volume 86 (3): 681
Fed of American Socs for Experimental Biology – Sep 1, 2009
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