In addition to the direct activation of inflammatory signaling pathways, cell death and the release of intracellular damage-associated molecular patterns also likely contribute to the inflammatory response seen after the administration of chemotherapy. Potent immune activators such high mobility group box 1 are released and signal via toll-like receptors to activate NFkB leading to cytokine production. Interestingly, despite BEZ235 evidence of tissue inflammation and Vismodegib clinical trial corticosterone release, we did not observe a significant increase in circulating inflammatory cytokines 4 hours after chemotherapy administration. It is possible that circulating cytokines may be elevated at a shorter time point after chemotherapy administration, returning to baseline after 4 hours. Alternately, chemotherapy may produce localized inflammation within the CNS leading to HPA axis activation. Although the direct action of cytokines on skeletal muscle is a well-documented mechanism of atrophy, the data presented here are consistent with a growing body of evidence demonstrating that CNS inflammation is all that is required for HPA axis activation and muscle atrophy. A large body of evidence supports the necessity of NFkB activation in skeletal myocytes for the development of atrophy. NFkB activity is increased in response to multiple atrophic stimuli and genetic blockade of this pathway protects against atrophy in response to denervation as well as tumor growth. Chemotherapy also increases NFkB DNA binding in skeletal muscle and has been proposed the driver of muscle atrophy in this setting. This is seemingly at odds with our finding that glucocorticoid signaling, known to antagonize inflammatory pathways, is required for muscle atrophy in this proinflammatory state. However, our results are consistent with an emerging body of literature demonstrating that under certain physiologic conditions, glucocorticoids potentiate rather than inhibit immune responses. Indeed, it appears that glucocorticoid levels within the physiologic range are permissive for a normal early immune response and only become suppressive at higher doses over longer time courses.