More MS news articles for August 2002

IL-1 Leads to Inflammatory Response That Exacerbates Damage After Brain Injury

Jul 31, 2002
By Karla Gale
NEW YORK (Reuters Health)

Microglial activation, exogenous macrophage infiltration, and the induction of proinflammatory cytokines--which normally contribute to severe neuronal injury after brain injury--are abrogated in transgenic mice lacking receptors for interleukin-1, according to a study published in the July 15th issue of the Journal of Neuroscience.

Dr. Steven W. Levison, of the Pennsylvania State College of Medicine in Hershey, and colleagues believe this finding points to possible therapeutic strategies for managing several types of brain damage.

The researchers compared the response to penetrating neocortical injury observed in wild-type mice and in mice with a null mutation in the interleukin-1 receptor gene. At 24 hours post-injury, the IL-1R1-null mice exhibited very few amoeboid microglia, whereas an abundance were observed in normal mice. There was also no evidence of peripheral macrophage infiltration in the mutant mice.

Even before the injury, the receptor-negative mice showed low basal levels of cyclooxygenase-2 compared with the wild-type mice. Two days afterward, COX-2 expression had increased about 100% in the normal mice and by only 5% in the mutant mice. At day 7, the increases were 150% and 40% above the control conditions, but the knockout mice still did not exhibit the levels seen in the wild-type mice before injury.

As a result of the diminished COX-2 response, the synthesis of prostanoids, which induce edema, and the production of reactive oxygen species are also likely to be inhibited by blocking the IL-1 receptor.

The investigators also observed blunted astrogliosis and decreased expression of IL-6 and IL-1-beta. In contrast, levels of tumor necrosis factor-alpha and nerve growth factor were unaffected by the null mutation. This is encouraging, the authors suggest, because "several of the adaptive responses of astroglial cells to injury would remain unperturbed when IL-1 is antagonized."

The Pennsylvania-based investigators suggest that antagonizing IL-1 could be of therapeutic benefit not only during the period following traumatic brain injury but also in ameliorating effects of stroke, multiple sclerosis, and Alzheimer's disease.

In an interview with Reuters Health, Dr. Levison pointed out that COX-2 inhibitors have been shown to slow the onset of Alzheimer's disease. "What's important in our findings is that IL-1 is upstream of COX-2. If IL-1 is knocked out, not only are the effects of COX-2 lost, but also other events that recruit cells to the brain are abrogated," he said.

Dr. Levison added that ideal candidates to block IL-1 would be antibodies to IL-1 or small molecular inhibitors of this signaling cascade.

J Neurosci 2002;22:6071-6082.

© 2002 Reuters Ltd