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Tumor Necrosis Factor-regulated Biphasic Activation of NF-κB Is Required for Cytokine-induced Loss of Skeletal Muscle Gene Products*

K. Ladner,M. Caligiuri,D. Guttridge

Published 2002 in Journal of Biological Chemistry

ABSTRACT

NF-κB activation is classically defined as a transient response initiated by the degradation of IκB inhibitor proteins leading to nuclear import of NF-κB and culminating with the resynthesis of IκBα and subsequent inactivation of the transcription factor. Although this type of regulation is considered the paradigm for NF-κB activation, other regulatory profiles are known to exist. By far the most common of these is chronic or persistent activation of NF-κB. In comparison, regulation of NF-κB in a biphasic manner represents a profile that is scarcely documented and whose biological significance remains poorly understood. Here we show using differentiated skeletal muscle cells, that tumor necrosis factor (TNF) induces NF-κB activation in a biphasic manner. Unlike the first transient phase, which is terminated within 1 h of cytokine addition, the second phase persists for an additional 24–36 h. Biphasic activation is mediated at both the levels of NF-κB DNA binding and transactivation function, and both phases are dependent on the IKK/26 S proteasome pathway. We find that regulation of the first transient phase is mediated by the degradation and subsequent resynthesis of IκBα, as well as by a TNF-induced expression of A20. Second phase activity correlates with persistent down-regulation of both IκBα and IκBβ proteins, derived from a continuous TNF signal. Finally, we demonstrate that inhibition of NF-κB prior to initiation of the second phase of activity inhibits cytokine-mediated loss of muscle proteins. We propose that the biphasic activation of NF-κB in response to TNF may play a key regulatory role in skeletal muscle wasting associated with cachexia.

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