High-mobility group protein 1 (HMG-1), which only recently ascribed cytokine-like functions, is now implicated in the etiology of sickness behavior.1 HMG-1 is a small, dipolar protein that is heavily modified post-translationally and highly conserved evolutionarily.2,3
Classically, it has been described as a non-histone chromosomal protein transcription and replication regulator, as a nucleosome stabilizer, and as a neurite outgrowth mediator.1-4 HMG-1 has since been described as a late mediator of endotoxemia, sepsis, inflammation, and now, sickness behavior.1,5
The behavioral depression, food aversion, malaise, aches, and fever typically associated with illness (collectively dubbed sickness behavior) are not the result of infection-induced debilitation but rather of a coordinated immune response in the form of peripheral cytokines acting on central targets.6-8 Infectious agent detection elicits pro-inflammatory cytokine release in the periphery, which is signaled via both a fast neuronal and a slow humoral pathway to the brain.8 Substance P and cholecystokinin-independent neuronal afferents to the hypothalamus, as well as other brain regions, elevate central levels of pro-inflammatory cytokines, particularly IL-1 beta and TNF-alpha.6,7 Vascular epithelium at blood-brain-barrier-deficient sites produces the freely diffusible prostaglandin E2 (PGE2), via the action of cyclooxygenase-2 (COX-2), which then acts on potentially distant brain regions provoking the generation of IL-1 beta and TNF-alpha as well.8 IL-1 beta and TNF-alpha have long been known as the major early mediators of endotoxemia, exerting their effects in as little as a few hours.7 Specifically, IL-1 beta is implicated in behavioral depression, while IL-6 (induced by IL-1 beta) is associated with fever. Both IL-1 beta and IL-6 exert their effects via actions on the hypothalamic-pituitary-adrenal (HPA) axis.7,8
|Figure 1. Peripheral infection signals central elevation of pro-inflammatory factors that act on the HPA axis to elicit sickness behavior. IL-1 beta and TNF-alpha are released first. IL-1 beta induces release of IL-6. IL-1 beta and TNF-alpha, with the help of IFN-gamma and LPC, elicit HMG-1 release subsequently. All feed back to perpetuate the release of pro-inflammatory factors.
IL-1 beta and TNF-alpha act synergistically with IFN-gamma and lysophosphatidylcholine (LPC) to induce HMG-1 release after several hours, hence HMG-1 has been referred to as a late mediator of endotoxemia.9,10 HMG-1, however, does not have a leader sequence that would target it for secretion.9,10 Instead, it diffuses from the nucleus into the cytoplasm where, by some unknown mechanism, it enters calcium-dependent secretory lysosomes that are later exocytosed.10 Delay in HMG-1 release is not accomplished merely by complex trafficking but also by LPC itself. The appearance of LPC at the inflammation site is delayed several hours after infection due to the tardy appearance of phospholipase A2 (PLA2), the enzyme responsible for its conversion from phosphatidylcholine (PC).10 HMG-1 feeds back, likely via binding the receptor for advanced glycation endproducts (RAGE) and promotes further release of pro-inflammatory cytokines.1,3,9,11 Most recently, HMG-1 has been implicated in the food aversion, hypophagia, anorexia, and weight loss aspects of sickness behavior via its action on the HPA axis. In this way, HMG-1, IL-1 beta, and IL-6 are mobilized after infection through tightly regulated spatial and temporal mechanisms to elicit the food aversion, depression, and fever behaviors associated with sickness.1,7-9
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