Cytokines and neuropeptides are modulators of neuroimmunoregulation in the central nervous system (CNS). The interaction of these modulators may have important implications in CNS diseases. We investigated whether interleukin-1beta (IL-1beta) modulates the expression of neurokinin-1 receptor (NK-1R), the primary receptor for substance P (SP), a potent neuropeptide in the CNS. IL-1beta upregulated NK-1R expression in human astroglioma cells (U87 MG) and primary rat astrocytes at both mRNA and protein levels. IL-1beta treatment of U87 MG cells and primary rat astrocytes led to an increase in cytosolic Ca(2+) in response to SP stimulation, indicating that IL-1beta-induced NK-1R is functional. CP-96,345, a specific non-peptide NK-1R antagonist, inhibited SP-induced rise of [Ca(2+)](i) in the astroglioma cells. Investigation of the mechanism responsible for IL-1beta action revealed that IL-1beta has the ability of activating nuclear factor-kappab (NF-kappaB). Caffeic acid phenethyl ester (CAPE), a specific inhibitor of NF-kappaB activation, not only abrogated IL-1beta-induced NF-kappaB promoter activation, but also blocked IL-1beta-mediated induction of NK-1R gene expression. These findings provide additional evidence that there is a biological interaction between IL-1beta and the neuropeptide SP in the CNS, which may have important implications in the inflammatory diseases in the CNS.
(c) 2004 Wiley-Liss, Inc.