Cytokines: How important are they in mediating sickness?

Sickness refers to a set of coordinated physiological and behavioral changes in response to systemic inflammation. It is characterized by fever, malaise, social withdrawal, fatigue, and anorexia. While these responses collectively represent a protective mechanism against infection and injury, increasing lines of evidence indicate that over-exaggerated or persistent sickness can damage the brain, and could possibly raise the risk to developing delirium. Therefore, a clear understanding in sickness will be beneficial. It has long been believed that sickness results from increased systemic cytokines occurring during systemic inflammation. However, in recent years more and more conflicting data have suggested that development of sickness following peripheral immune challenge could be independent of cytokines. Hence, it is confusing as to whether cytokines really do act as primary mediators of sickness, or if they are secondary to alternative inducing factor(s). In this review, we will (1) introduce the relationships between systemic inflammation, cytokines, sickness, and delirium, and (2) attempt to interpret the recent controversies.