Cytokines and the regulation of hypoxia-inducible factor (HIF)-1alpha.

Hypoxia-inducible factor (HIF)--an oxygen sensor? The HIF-oxygen sensing association type of dogma is, unequivocally, well anchored. But this is only one face of, at least, a double-sided coin. Current concepts charge HIF of taking sides with a yet not well-founded identity--an immunologic sensor and/or regulator. Or, is it really a sensor, put it more correctly, a key player in sensing mechanisms? The evolving association between HIF and immunity emanates from an established linkage that bonds oxidative stress and inflammation--notably the 'biologic response modifiers', or cytokines. HIF is a redox(y)-sensitive transcription factor, and so are cytokines. Recently, cytokines emerged as major regulators of HIF, under physiologic conditions extending the realm of hypoxia. Alternatively, can HIF, like the so infamous inflammatory transcription factor NF-(kappa)B, prove itself as a key player in the regulation of cytokines and, subsequently, the inflammatory process. The targeting of HIF would be, at least theoretically, of therapeutic value, but does it make sense given its intricate role in hypoxia signaling? It is the theme of HIF being an immunologic sensor that will be explored therein--with special emphasis on the regulatory role of cytokines.