Cytokines are a large family of soluble, low-molecular-weight proteins that influence both immune and nonimmune systems. They are produced by a variety of cells including monocytes, macrophages, glial cells, and endothelial and epithelial cells.16 Several different stimuli including trauma, infection, and reperfusion injury cause cytokine release, specifically increases in IL-6, TNF-α, and IL-1. These proinflammatory cytokines are key to the development of the immediate response to the insult, with further release of inflammatory mediators, changes in leukocyte traffic, and cardiovascular function. Cytokines also play a role in peripheral and central nociception, as shown by Watkins and Maier.17 For example, proinflammatory cytokines able to induce hyperalgesia at the site of an inflammatory insult18 have been shown to stimulate the formation of prostaglandins peripherally, resulting in sensitization of peripheral, or "silent," nociceptors.17,19 In addition, prostaglandin E2 is released locally as a result of surgical tissue disruption and can suppress inflammatory host responses including natural killer (NK) cell cytotoxicity.20,21 Cytokines such as IL-1, IL-6, and TNF-α also modulate nociception via their effects on a range of molecules in the brain, in particular prostaglandins such as prostaglandin E2.18 Prostaglandins are a likely mechanism by which cytokines in the brain mediate pain responses. Brain-derived cytokines modulate additional functions controlled in the hypothalamus, such as thermoregulation, and can disturb sleep and feeding activities.22 These are symptoms commonly seen in patients with sepsis.