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Sex Difference in Link between Interleukin-6 and Stress

Departments of Biomedical Sciences (R.J., J.R.T., J.C.S., J.C., V.K.G., E.M.P., M.H.L.) and Animal Sciences (D.H.K.), College of Veterinary Medicine, and Dalton Cardiovascular Research Center (J.C.S., E.M.P.), University of Missouri, Columbia, Missouri 65211

Address all correspondence and requests for reprints to: Ryan Jankord, Ph.D., Department of Psychiatry, University of Cincinnati, Genome Research Institute, E205, 2170 East Galbraith Road, Cincinnati, Ohio 45237. E-mail: ryan.jankord{at}uc.edu.

Inflammation contributes to disease development, and the neuroimmunoendocrine interface is a potential site of action for inflammatory products like IL-6 to affect health. Although plasma IL-6 can stimulate the activity of the hypothalamo-pituitary-adrenocortical (HPA) axis, the precise role, if any, for IL-6 in the HPA response to nonimmunological stressors is unclear. The purpose of this study was to test the hypothesis that IL-6 in the stalk median eminence (SME) can be directly involved in stimulating ACTH secretion in response to acute stress in female swine. This study was undertaken as a result of finding IL-6 localized to the external zone of the SME next to the hypophyseal portal vessels. Results indicate that content of IL-6 in the SME decreases in response to acute stress along with an increase in nuclear phosphorylated signal transducer and activator of transcription-3 (pSTAT-3) in pituitary corticotrophs and a simultaneous increase in plasma concentrations of IL-6 and ACTH. Furthermore, we show that females concomitantly display greater SME content of IL-6 and greater HPA responsiveness to stress, thereby suggesting that IL-6 release from the SME is an integral factor contributing to enhanced stress responsiveness in females. Our results provide evidence for a direct link between IL-6 and ACTH release and reveal a sex difference in this relationship.

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