FIG. 8.

FTH prevents pro-oxidant labile Fe from sustaining JNK activation. FTH controls JNK activation indirectly via a mechanism that prevents labile iron from partaking in the production of free radicals via the Fenton chemistry. This is consistent with previous studies showing that reducing free radical production is sufficient per se to control JNK activity, via inhibition of redox-sensitive phosphatases regulating JNK activity (not illustrated). Presumably, the mechanism underlying the cytotoxic effect of JNK activation involves the inhibition of FTH expression, which promotes cellular Fe overload, accumulation of free radicals, and programmed cell death. This functional cross talk between FTH and JNK controls the host metabolic adaptation to tissue Fe overload during systemic infections. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars