High physiological levels of the stress hormone, corticosterone (CORT), exacerbate brain inflammatory responses to lipopolysaccharide (LPS) and to the nerve agent, DFP: role in Gulf War Illness?
Gulf War Illness (GWI) is a multi-symptom disorder with features characteristic of "sickness" behavior including, cognitive impairment, fatigue, depression, sleep disruption, GI and dermatological problems. Typically, sickness behavior is the normal manifestation of an inflammatory response to infection or injury and one that resolves with restoration of homeostasis. In GWI, the symptoms persist, findings suggestive of a heightened or chronic neuroimmune/neuroinflammatory reaction, the basis for which remains unknown. Undeniably, exposure of humans to infectious agents, or even acetylcholinesterase inhibitors presumed to be responsible for GWI, has occurred without the development of chronic sickness behavior and chronic peripheral/CNS inflammatory responses. Therefore, the question remains as to what combination of exposures and the environment of the 1991 Gulf War led to GWI. One answer may relate to a heightened physiological stress response associated with the short-term battlefield environment. Recent evidence suggests that the stressful environment under which troops operated may have altered the BBB and led to a stress/agent interaction unique to the first Gulf War. In support of this possibility, we found that one week of exposure to high physiological levels of CORT in the mouse results in an augmented neuroinflammatory response (induction of IL1-beta, TNF-alpha and IL-6 mRNA) to challenge by the inflammogen, LPS; in contrast, acute exposure to CORT blocks the neuroinflammatory response to LPS. Moreover, we also found an enhanced expression of some proinflammatory cytokines in brain (TNF-alpha & IL-6) following exposure to the nerve agent, DFP. One week of prior exposure to CORT augmented these effects of DFP. Together, these observations are suggestive of a possible unrecognized link between the stressful environment of the Gulf War theater, agent exposures unique to this war, and a resulting adverse and persistent neuroinflammatory outcome.
The Toxicologist. Society of Toxicology 48th Annual Meeting and ToxExpo, March 15-19, 2009, Baltimore, Maryland