Interleukins, signal transduction, and the immune system-mediated stress response.

Overwhelming evidence indicates that the administration of cytokines such as IL-1 alpha and beta, IL-6, and TNF-1 alpha stimulates one or more components of the HPA axis. The hypothesis driving this research is that host infection and tissue injury trigger the synthesis and release of several cytokines that act locally at sites of trauma and distally upon entering the circulation. Available evidence suggests that the primary source of HPA axis-acting or circulating cytokines is activated monocytes or macrophages; therefore, a direct relationship should exist between the appearance of monokines in plasma and the subsequent appearance of pituitary-adrenocortical hormones in plasma as well. Clarification of the physiological role of monokines as mediators of the host stress response will come from in vivo studies in which the type, sequence of appearance, duration of elevation, and quantification of each monokine is monitored along with ACTH and glucocorticoids, following an appropriate immune challenge. In several recent reports, investigators have administered bacterial-derived endotoxin or LPS to stimulate the physiological events associated with infection or injury and chronicled plasma levels of IL-1, IL-6, and TNF-alpha (37,56,57). In human subjects, endotoxin challenge enhanced plasma TNF-alpha levels by 1 hour, which returned to basal levels by 4 hours (37), whereas, IL-6 plasma activity increased at 2 hours post-challenge and returned to baseline by 6 hours (56). Thus, both of these monokines are implicated as possible acute activators of the HPA axis. In perhaps the most revealing study to date, LPS challenge of mice indicated both a differential appearance and disappearance rate in serum for TNF-alpha and IL-1 and a differential regulation of these monokines by glucocorticoid feedback (57). Serum TNF was detected 45 minutes post-LPS, peaked by 1 hour, and returned to control levels by 3 hours. Serum corticosterone concentrations rose rapidly over a time course similar to that of TNF. Even after serum TNF concentration had returned to basal conditions, corticosterone levels remained maximally elevated, and serum corticosterone was still significantly above basal levels 24-hour post-LPS. The rapid return of circulating TNF to pre-LPS challenge levels appeared to be regulated by negative glucocorticoid feedback, because TNF remained maximally elevated for at least 6 hours in adrenalectomized or hypophysectomized mice. LPS-induced levels of IL-1 were delayed as compared to serum TNF, peaked at 4 hours, and remained elevated even at 24 hours.(ABSTRACT TRUNCATED AT 400 WORDS)