Interleukin-1beta (IL-1beta) is a cytokine that regulates a variety of biological processes. In addition to its traditional role in the immune system, IL-1beta plays an integral role in neural-immune and developmental processes in the nervous system. The pleiotropic ability of IL-1beta may be due to the activation of different signal transduction mechanisms in specific cell types or under certain cellular conditions. We have previously demonstrated that IL- regulates healing and repair in the developing, mammalian nervous system. In the damaged perinatal mouse brain, IL-1beta is expressed in astrocytes that change from a stellate to a spindle-shaped morphology. The spindle-shaped astrocytes enclose the wound, separating the healthy from damaged neural tissue. The shape change and subsequent repair processes are IL-1beta activity-dependent, acting through the IL-1 type 1 receptor (IL-1R1), as co-application of the IL-1type 1 receptor antagonist protein (IL-1ra) blocks IL-1beta induced effects. In the C6 astrocytic cell line, IL-1beta induced similar shape changes and upregulated expression of the cytoskeletal protein, glial fibrillary acidic protein (GFAP). Since cytoskeletal changes, as well as specific signal transduction mechanisms, are associated with increases in intracellular calcium ([Ca2+]i), studies were carried out to determine if increases in [Ca2+]i induced by IL-1beta occurred through activation of the IL-1R1 in C6 cells. Cells were treated with IL-1beta and/or IL-1ra, followed by measurement of relative changes in [Ca2+]i using fura-2 fluorescence imaging methods. IL-1beta increased [Ca2+]i levels in a dose and time dependent manner. Treatment with IL-1ra blocked IL-1beta induced increases in [Ca2+]i, indicating that IL-1beta acts through the IL-1R1. Immunocytochemistry experiments showed that untreated C6 cells normally express IL-1beta, IL-1ra, and IL-1RI. Thus, IL-1 system molecules may play a role in normal C6 astrocyte physiology.