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The Journal of Neuroscience, September 26, 2007, 27(39):10476-10486; doi:10.1523/JNEUROSCI.3357-07.2007

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Behavioral/Systems/Cognitive
Endothelial-Specific Knockdown of Interleukin-1 (IL-1) Type 1 Receptor Differentially Alters CNS Responses to IL-1 Depending on Its Route of Administration

San Ching,^1 * Hao Zhang,^1 * Natalya Belevych,¹ Lingli He,¹ Wenmin Lai,¹ Xin-an Pu,² Laura B. Jaeger,³ Qun Chen,¹ and Ning Quan¹

¹Department of Oral Biology and ²Center for Neurobiology, Ohio State University, Columbus, Ohio 43210-1094, and ³Department of Pharmacology and Physiology, St. Louis University, St. Louis, Missouri 63106

Correspondence should be addressed to Ning Quan, 4179 Postle Hall, 305 West 12th Avenue, Columbus, OH 43210-1094. Email: quan.14{at}osu.edu

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.

Key words: cytokine; neuroimmune; blood–brain barrier; fever; locomotor activity; illness behavior

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Received Oct. 6, 2006; revised Aug. 8, 2007; accepted Aug. 9, 2007.

Correspondence should be addressed to Ning Quan, 4179 Postle Hall, 305 West 12th Avenue, Columbus, OH 43210-1094. Email: quan.14{at}osu.edu

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