Inflammation occurs as a consequence of brain injury, and results in the production of inflammatory cytokines, which contribute to the progression of the insult. One of the most potent inflammatory cytokines is interleukin-1 (IL-1), which is induced by many types of brain injury and can potentiate neuronal loss. IL-1 inhibitors have been suggested as therapeutic tools following brain injury to attenuate neuronal loss. However, IL-1? is also expressed in the brain under physiological conditions, and may play a role in mediating normal hippocampal function. We have previously demonstrated that IL-1? activates distinct signaling pathways in neurons versus glial cells in the brain. Therefore, to assess the consequences of inflammation that occur following injury, and the potential therapeutic value of inhibiting inflammation, it is critical to understand the cell-specific consequences and to distinguish physiological versus pathophysiologial roles for this key cytokine. IL-1 signals via a receptor complex composed of the type 1 IL-1 receptor (IL-1R1) and the IL-1 Receptor Accessory Protein (IL-1RAcP). A novel isoform of the IL-1RAcP, termed AcPb, has been identified that is expressed exclusively in CNS neurons, providing a new opportunity to investigate the mechanisms governing neuron-specific IL- 1 actions. To identify the function of the neuron-specific IL-1RAcPb we will establish neuronal cultures from AcPb-/- mice compared to wild type neurons and to neurons lacking both isoforms of the protein (AcP-/-). The effects of IL-1? on these neurons will be analyzed to determine the role of AcPb in mediating neuron-specific signaling pathways, and the consequences for neuronal function.

Public Health Relevance

Interleukin-1 is a potent and pleiotropic cytokine that is induced in the brain by injury, disease, and stress. The recent identification of a neuron-specific isoform of a key IL-1 signaling protein provides a novel opportunity to investigate mechanisms governing the specific effects of IL-1 on neuronal function. These studies may also facilitate the development of therapeutic approaches to distinguish physiological versus pathophysiologial roles for this key cytokine in the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS076867-02
Application #
8330233
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Mamounas, Laura
Project Start
2011-09-15
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$193,750
Indirect Cost
$68,750
Name
Rutgers University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
130029205
City
Newark
State
NJ
Country
United States
Zip Code
07102
Huang, Yangyang; Smith, Dirk E; Ibáñez-Sandoval, Osvaldo et al. (2011) Neuron-specific effects of interleukin-1? are mediated by a novel isoform of the IL-1 receptor accessory protein. J Neurosci 31:18048-59