TY - JOUR
T1 - Influence of hypothalamic IL-6/gp130 receptor signaling on the HPA axis response to chronic stress
AU - Girotti, Milena
AU - Donegan, Jennifer J.
AU - Morilak, David A.
N1 - Funding Information:
This work was supported by research grant MH053851 from the National Institute of Mental Health , which had no further role in study design, collection, analysis or interpretation of data, nor in the preparation or decision to submit the paper for publication.
PY - 2013/7
Y1 - 2013/7
N2 - Abnormal basal activity and stress-evoked reactivity of the hypothalamic-pituitary-adrenal (HPA) axis are often seen in depression, implicating HPA axis dysfunction as a potentially causative or exacerbating factor. Chronic stress is also a factor in depression, but it is not known what may underlie the shift from adaptive to maladaptive HPA activity over the course of chronic stress. Interleukin 6 (IL-6), a stress-inducible cytokine that signals through gp130 and IL-6Rα receptors to activate the JAK/STAT3 signaling cascade, is elevated in some subtypes of depression, and may have a modulatory effect on HPA activation, raising the possibility that IL-6 contributes to depression through effects on the HPA axis. In this study, we examined the effects of three different stress modalities, acute footshock, chronic intermittent cold (CIC) stress and chronic unpredictable stress (CUS) on IL-6 signaling in the hypothalamus. We also investigated whether IL-6 modulates the HPA response to chronic stress, by blocking IL-6 signaling in the brain during CIC stress using either a neutralizing antibody or an inhibitor of STAT3 phosphorylation. We show that IL-6 and STAT3 in the hypothalamus are activated in response to footshock and CUS. We also found that basal IL-6 signaling through the JAK/STAT3 pathway is required for the sustained CORT response to chronic, but not acute, cold stress and therefore is a potential determinant of plasticity in the HPA axis specifically during chronic stress exposure.
AB - Abnormal basal activity and stress-evoked reactivity of the hypothalamic-pituitary-adrenal (HPA) axis are often seen in depression, implicating HPA axis dysfunction as a potentially causative or exacerbating factor. Chronic stress is also a factor in depression, but it is not known what may underlie the shift from adaptive to maladaptive HPA activity over the course of chronic stress. Interleukin 6 (IL-6), a stress-inducible cytokine that signals through gp130 and IL-6Rα receptors to activate the JAK/STAT3 signaling cascade, is elevated in some subtypes of depression, and may have a modulatory effect on HPA activation, raising the possibility that IL-6 contributes to depression through effects on the HPA axis. In this study, we examined the effects of three different stress modalities, acute footshock, chronic intermittent cold (CIC) stress and chronic unpredictable stress (CUS) on IL-6 signaling in the hypothalamus. We also investigated whether IL-6 modulates the HPA response to chronic stress, by blocking IL-6 signaling in the brain during CIC stress using either a neutralizing antibody or an inhibitor of STAT3 phosphorylation. We show that IL-6 and STAT3 in the hypothalamus are activated in response to footshock and CUS. We also found that basal IL-6 signaling through the JAK/STAT3 pathway is required for the sustained CORT response to chronic, but not acute, cold stress and therefore is a potential determinant of plasticity in the HPA axis specifically during chronic stress exposure.
KW - Chronic stress
KW - HPA axis
KW - Hypothalamus
KW - Interleukin 6
KW - JAK/STAT signaling
UR - http://www.scopus.com/inward/record.url?scp=84877921458&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84877921458&partnerID=8YFLogxK
U2 - 10.1016/j.psyneuen.2012.11.004
DO - 10.1016/j.psyneuen.2012.11.004
M3 - Article
C2 - 23218517
AN - SCOPUS:84877921458
SN - 0306-4530
VL - 38
SP - 1158
EP - 1169
JO - Psychoneuroendocrinology
JF - Psychoneuroendocrinology
IS - 7
ER -