Differential activation and antagonistic function of HIF-α isoforms in macrophages are essential for NO homeostasis (original) (raw)

  1. Ellen L. O'Dea2,
  2. Andrew Doedens1,
  3. Jung-whan Kim1,
  4. Alexander Weidemann1,
  5. Christian Stockmann1,
  6. Masataka Asagiri2,
  7. M. Celeste Simon3,
  8. Alexander Hoffmann2 and
  9. Randall S. Johnson1,4
  10. 1Division of Biology, University of California at San Diego, La Jolla, California 92093, USA;
  11. 2Signaling Systems Laboratory and Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California 92093, USA;
  12. 3Abramson Family Cancer Research Institute, University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania 19104, USA

Abstract

Hypoxic response and inflammation both involve the action of the hypoxia-inducible transcription factors HIF-1α and HIF-2α. Previous studies have revealed that both HIF-α proteins are in a number of aspects similarly regulated post-translationally. However, the functional interrelationship of these two isoforms remains largely unclear. The polarization of macrophages controls functionally divergent processes; one of these is nitric oxide (NO) production, which in turn is controlled in part by HIF factors. We show here that the HIF-α isoforms can be differentially activated: HIF-1α is induced by Th1 cytokines in M1 macrophage polarization, whereas HIF-2α is induced by Th2 cytokines during an M2 response. This differential response was most evident in polarized macrophages through HIF-α isoform-specific regulation of the inducible NO synthase gene by HIF-1α, and the arginase1 gene by HIF-2α. In silico modeling predicted that regulation of overall NO availability is due to differential regulation of HIF-1α versus HIF-2α, acting to, respectively, either increase or suppress NO synthesis. An in vivo model of endotoxin challenge confirmed this; thus, these studies reveal that the two homologous transcription factors, HIF-1α and HIF-2α, can have physiologically antagonistic functions, but that their antiphase regulation allows them to coordinately regulate NO production in a cytokine-induced and transcription-dependent fashion.

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