Endothelial-specific knockdown of interleukin-1 (IL-1) type 1 receptor differentially alters CNS responses to IL-1 depending on its route of administration.
Interleukin-1 (IL-1) has been implicated as a critical mediator of neuroimmune communication. In the brain, the functional receptor for IL-1, type 1 IL-1 receptor (IL-1R1), is localized primarily to the endothelial cells. In this study, we created an endothelial-specific IL-1R1 knockdown model to test the role of endothelial IL-1R1 in mediating the effects of IL-1. Neuronal activation in the hypothalamus was measured by c-fos expression in the paraventricular nucleus and the ventromedial preoptic area. In addition, two specific sickness symptoms, febrile response and reduction of locomotor activity, were studied. Intracerebroventricular injection of IL-1 induced leukocyte infiltration into the CNS, activation of hypothalamic neurons, fever, and reduced locomotor activity in normal mice. Endothelial-specific knockdown of IL-1R1 abrogated all these responses. Intraperitoneal injection of IL-1 also induced neuronal activation in the hypothalamus, fever, and reduced locomotor activity, without inducing leukocyte infiltration into the brain. Endothelial-specific knockdown of IL-1R1 suppressed intraperitoneal IL-1-induced fever, but not the induction of c-fos in hypothalamus. When IL-1 was given intravenously, endothelial knockdown of IL-1R1 abolished intravenous IL-1-induced CNS activation and the two monitored sickness symptoms. In addition, endothelial-specific knockdown of IL-1R1 blocked the induction of cyclooxygenase-2 expression induced by all three routes of IL-1 administration. These results show that the effects of intravenous and intracerebroventricular IL-1 are mediated by endothelial IL-1R1, whereas the effects of intraperitoneal IL-1 are partially dependent on endothelial IL-1R1.
Ching
San
S
Department of Oral Biology, Ohio State University, Columbus, Ohio 43210-1094, USA
Zhang
Hao
H
Belevych
Natalya
N
He
Lingli
L
Lai
Wenmin
W
Pu
Xin-an
XA
Jaeger
Laura B
LB
Chen
Qun
Q
Quan
Ning
N
D000818:Animals; D002490:Central Nervous System / Q000187:drug effects*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D042783:Endothelial Cells / Q000378:metabolism*; D005334:Fever / Q000503:physiopathology; D016762:Genes, fos / Q000502:physiology; D007031:Hypothalamus / Q000187:drug effects; D007155:Immunologic Factors / Q000008:administration & dosage*; D007375:Interleukin-1 / Q000008:administration & dosage*; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D015213:Neuroimmunomodulation / Q000187:drug effects; D053573:Receptors, Interleukin-1 Type I / Q000187:drug effects / Q000502:physiology*
D007155:Immunologic Factors; D007375:Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D051546:Cyclooxygenase 2