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The Journal of Neuroscience, July 15, 2002, 22(14):6071-6082
The Type 1 Interleukin-1 Receptor Is Essential for the Efficient
Activation of Microglia and the Induction of Multiple Proinflammatory
Mediators in Response to Brain Injury
Anirban
Basu,
J. Kyle
Krady,
Mark
O'Malley,
Scott D.
Styren,
Steven T.
DeKosky, and
Steven W.
Levison
Department of Neuroscience and Anatomy, Pennsylvania State
University College of Medicine, Hershey, Pennsylvania 17033, and
Department of Neurology, University of Pittsburgh, Pittsburgh,
Pennsylvania 15213
Interleukin-1 (IL-1) is induced immediately after insults to the
brain, and elevated levels of IL-1 have been strongly implicated in the
neurodegeneration that accompanies stroke, Alzheimer's disease, and
multiple sclerosis. In animal models, antagonizing IL-1 has been shown
to reduce cell death; however, the basis for this protection has not
been elucidated. Here we analyzed the response to penetrating brain
injury in mice lacking the type 1 IL-1 receptor (IL-1R1) to determine
which cellular and molecular mediators of tissue damage require IL-1
signaling. At the cellular level, fewer amoeboid microglia/macrophages
appeared adjacent to the injured brain tissue in IL-1R1 null mice, and
those microglia present at early postinjury intervals retained their
resting morphology. Astrogliosis also was mildly abrogated. At the
molecular level, cyclooxygenase-2 (Cox-2) and IL-6 expression were
depressed and delayed. Interestingly, basal levels of Cox-2, IL-1, and
IL-6 were significantly lower in the IL-1R1 null mice. In addition, stimulation of vascular cell adhesion molecule-1 mRNA was
depressed in the IL-1R1 null mice, and correspondingly, there was
reduced diapedesis of peripheral macrophages in the IL-1R1 null brain after injury. This observation correlated with a reduced number of
Cox-2+ amoeboid phagocytes adjacent to the injury.
In contrast, several molecular aspects of the injury response were
normal, including expression of tumor necrosis factor- and the
production of nerve growth factor. Because antagonizing IL-1 protects
neural cells in experimental models of stroke and multiple sclerosis,
our data suggest that cell preservation is achieved by abrogating
microglial/macrophage activation and the subsequent self-propagating
cycle of inflammation.
Key words:
cytokines; IL-1; IL-6; TNF-; traumatic brain injury; prostaglandins; astrocytes; null mutant mice
Copyright © 2002 Society for Neuroscience 0270-6474/02/22146071-12$05.00/0
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